201 results on '"Daiber A"'
Search Results
2. Tobacco smoking and vascular biology and function: evidence from human studies.
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Hahad, Omar, Kuntic, Marin, Kuntic, Ivana, Daiber, Andreas, and Münzel, Thomas
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TOBACCO smoke ,SMOKING ,CIGARETTE smoke ,BIOLOGY ,CARDIOVASCULAR diseases risk factors - Abstract
Tobacco cigarette smoking is among the most complex and least understood health risk factors. A deeper insight into the pathophysiological actions of smoking exposure is of special importance as smoking is a major cause of chronic non-communicable diseases, in particular of cardiovascular disease as well as risk factors such as atherosclerosis and arterial hypertension. It is well known that smoking exerts its negative effects on cardiovascular health through various interdependent pathophysiological actions including hemodynamic and autonomic alterations, oxidative stress, inflammation, endothelial dysfunction, thrombosis, and hyperlipidemia. Importantly, impaired vascular endothelial function is acknowledged as an early key event in the initiation and progression of smoking-induced atherosclerosis. Increasing evidence from human studies indicates that cigarette smoke exposure associates with a pathological state of the vascular endothelium mainly characterized by reduced vascular nitric oxide bioavailability due to increased vascular superoxide production. In the present overview, we provide compact evidence on the effects of tobacco cigarette smoke exposure on vascular biology and function in humans centered on main drivers of adverse cardiovascular effects including endothelial dysfunction, inflammation, and oxidative stress. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Deficiency of Antioxidative Paraoxonase 2 (Pon2) Leads to Increased Number of Phenotypic LT-HSCs and Disturbed Erythropoiesis
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Lisa Spiecker, Daniel Sasca, Andrea Schüler, Piyush More, Ines Witte, Victoria Petermann, Markus Meyerhöfer, Julia Mehlig, Viral N. Shah, Nina Cabezas-Wallscheid, Thomas Kindler, Andreas Daiber, Sven Horke, Andrea Pautz, Hartmut Kleinert, and Patricia S. Haehnel
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Premature aging ,Aging ,Myeloid ,Article Subject ,Biology ,Biochemistry ,CXCR4 ,Antioxidants ,Cell Line ,Mice ,medicine ,Animals ,Erythropoiesis ,Progenitor cell ,QH573-671 ,Aryldialkylphosphatase ,Cell Differentiation ,Cell Biology ,General Medicine ,Hematopoietic Stem Cells ,Cell biology ,Haematopoiesis ,Phenotype ,medicine.anatomical_structure ,Bone marrow ,Stem cell ,Reactive Oxygen Species ,Cytology ,Research Article - Abstract
Background. Long-term hematopoietic stem cells (LT-HSCs) reside in bone marrow niches with tightly controlled reactive oxygen species (ROS) levels. ROS increase results into LT-HSC differentiation and stem cell exhaustion. Paraoxonase 2 (PON2) has been shown to be important for ROS control. Objectives. We investigate the effects of inactivation of the PON2 gene on hematopoietic cell differentiation and activity. Methods and Results. In young mice with inactivated Pon2 gene (Pon2-/-, -/- BM outcompeted WT BM at early time points. ROS levels were significantly increased in Pon2-/- whole BM, but not in Pon2-/- LT-HSCs. In more differentiated stages of hematopoiesis, Pon2 deficiency led to a misbalanced erythropoiesis both in physiologic and stress conditions. In older mice (>9 months), Pon2 depletion caused an increase in LT-HSCs as well as increased levels of granulocyte/macrophage progenitors (GMPs) and myeloid skewing, indicating a premature aging phenotype. No significant changes in ROS levels in old Pon2-/- LT- and short-term (ST-) HSCs were observed, but a significant reduction of spontaneous apoptotic cell death was measured. RNA-seq analysis in Pon2-/- LT-HSCs identified overrepresentation of genes involved in the C-X-C chemokine receptor type 4 (Cxcr4) signaling, suggesting compensatory mechanisms to overcome ROS-mediated accelerated aging in hematopoietic progenitor cells. Conclusions. In summary, our current data indicate that PON2 is involved in the regulation of HSC functions.
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- 2021
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4. Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases
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Andreas Daiber, Pedro Felipe Malacarne, Xinxin Ding, Anna Gajos-Draus, Stefan Offermanns, Melina Lopez, Ralf P. Brandes, Jon O. Lundberg, and Flávia Rezende
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0301 basic medicine ,Aldehyde dehydrogenase ,Pharmacology ,Mice ,Nitroglycerin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cytochrome P-450 Enzyme System ,Animals ,Pentaerythritol Tetranitrate ,ddc:610 ,Nitrite ,Biotransformation ,Vascular tissue ,Nitrates ,biology ,Chemistry ,Cytochrome P450 ,Cytochrome P450 reductase ,Metabolism ,Monooxygenase ,030104 developmental biology ,biology.protein ,Microsome ,030217 neurology & neurosurgery - Abstract
Background and Purpose Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here. Experimental Approach As all CYPs depend on cytochrome P450 reductase (POR) as electron donor, we generated a smooth muscle cell-specific, inducible knockout mouse of POR (smcPOR−/−) to investigate the contribution of POR/CYP to vascular biotransformation of organic nitrates. Key Results Microsomes containing recombinant CYPs expressed in human vascular tissues released nitrite from NTG and PETN with CYP2C9 and CYP2C8 being most efficient. SFK525, a CYP suicide inhibitor, blocked this effect. smcPOR−/− mice exhibited no obvious cardiovascular phenotype (normal cardiac weight and endothelium-dependent relaxation) and plasma and vascular nitrite production was similar to control (CTL) animals. NTG- and PETN-induced relaxation of isolated endothelium-intact or endothelium-denuded vessels were identical between CTL and smcPOR−/−. Likewise, nitrite release from organic nitrates in aortic rings was not affected by deletion of POR in smooth muscle cells (SMCs). In contrast, inhibition of ALDH2 by benomyl (10 μM) inhibited NTG-induced nitrite production and relaxation. Deletion of POR did not modulate this response. Conclusions and Implications Our data suggest that metabolism by vascular CYPs does not contribute to the pharmacological function of organic nitrates.
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- 2021
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5. Disturbed Lipid Metabolism in Diabetic Patients with Manifest Coronary Artery Disease Is Associated with Enhanced Inflammation
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Ulrich Hink, Georg Daniel Duerr, Ryan Chaban, Matthias Oelze, Andreas Daiber, Thomas Münzel, Hendrik Treede, K. Buschmann, and Yves Gramlich
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medicine.medical_specialty ,Health, Toxicology and Mutagenesis ,Inflammation ,medicine.disease_cause ,Article ,Coronary artery disease ,Enos ,Diabetes mellitus ,Internal medicine ,medicine ,Humans ,oxidative stress ,biology ,business.industry ,dyslipidemia ,Public Health, Environmental and Occupational Health ,Lipid metabolism ,Lipid Metabolism ,medicine.disease ,biology.organism_classification ,Heme oxygenase ,Endocrinology ,nutrition ,Diabetes Mellitus, Type 2 ,inflammation ,diabetes mellitus ,Medicine ,medicine.symptom ,business ,chronic disease ,Diabetic Angiopathies ,Oxidative stress ,Dyslipidemia ,coronary artery disease - Abstract
Background: Diabetic vasculopathy plays an important role in the pathophysiology of coronary artery disease (CAD) with oxidative stress as a strong mediator. This study aims to elucidate the underlying pathomechanisms of diabetic cardiac vasculopathy leading to coronary disease with an emphasis on the role of oxidative stress. Therefore, novel insights into antioxidant pathways might contribute to new strategies in the treatment and prevention of diabetic CAD. Methods: In 20 patients with insulin-dependent or non-insulin dependent diabetes mellitus (IDDM/NIDDM) and 39 non-diabetic (CTR) patients, myocardial markers of oxidative stress, vasoactive proteins, endothelial nitric oxide synthase (eNOS), activated phosphorylated eNOS (p-eNOS), and antioxidant enzymes, e.g., tetrahydrobiopterin generating dihydrofolate reductase (DHFR), heme oxygenase (HO-1), as well as serum markers of inflammation, e.g., E-selectin, interleukin-6 (IL-6), and lipid metabolism, e.g., high- and low-density lipoptrotein (HDL- and LDL-cholesterol) were determined in specimens of right atrial tissue and in blood samples from type 2 diabetic and non-diabetic patients undergoing coronary artery bypass graft (CABG) surgery. Results: IDDM/NIDDM increased markers of inflammation (e.g., E-selectin, p = 0.005 and IL-6, p = 0.051), decreased the phosphorylated myocardial p-eNOS (p = 0.032), upregulated the myocardial stress response protein HO-1 (p = 0.018), and enhanced the serum LDL-/HDL-cholesterol ratio (p = 0.019). However, the oxidative stress markers in the myocardium and the expression of vasoactive proteins (eNOS, DHFR) showed only marginal adverse changes in patients with IDDM/NIDDM. Conclusion: Dyslipidemia and myocardial inflammation seem to be the major determinants of diabetic CAD complications. Dysregulation in pro-oxidative enzymes might be attributable to the severity of CAD and oxidative stress levels in all included patients undergoing CABG.
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- 2021
6. Aircraft noise exposure drives the activation of white blood cells and induces microvascular dysfunction in mice
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Matthias Oelze, Benjamin Philipp Ernst, Sebastian Strieth, Subao Jiang, Andreas Daiber, Yue Ruan, Katie Frenis, Sebastian Steven, Maria Teresa Bayo Jimenez, Thomas Münzel, Alex von Kriegsheim, Marin Kuntic, Huige Li, Omar Hahad, Adrian Gericke, Giovanny Rodriguez-Blanco, and Jonas Eckrich
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Male ,Proteomics ,medicine.medical_specialty ,Medicine (General) ,Aircraft ,QH301-705.5 ,Clinical Biochemistry ,Phagocytic NADPH oxidase ,Inflammation ,Video microscopy ,medicine.disease_cause ,Biochemistry ,Mice ,R5-920 ,Internal medicine ,medicine ,Leukocytes ,Animals ,Endothelial dysfunction ,Micorvascular dysfunction ,Aircraft noise exposure ,Biology (General) ,NADPH oxidase ,biology ,business.industry ,Dorsal skinfold model ,Organic Chemistry ,NADPH Oxidases ,Blood flow ,medicine.disease ,Pathophysiology ,Mice, Inbred C57BL ,Red blood cell ,Oxidative Stress ,Endocrinology ,medicine.anatomical_structure ,Plasma proteome ,Microvascular dysfunction ,biology.protein ,medicine.symptom ,business ,Doreal skinfold model ,Oxidative stress ,Inflammatory phenotype ,Research Paper - Abstract
Epidemiological studies showed that traffic noise has a dose-dependent association with increased cardiovascular morbidity and mortality. Whether microvascular dysfunction contributes significantly to the cardiovascular health effects by noise exposure remains to be established. The connection of inflammation and immune cell interaction with microvascular damage and functional impairment is also not well characterized. Male C57BL/6J mice or gp91phox−/y mice with genetic deletion of the phagocytic NADPH oxidase catalytic subunit (gp91phox or NOX-2) were used at the age of 8 weeks, randomly instrumented with dorsal skinfold chambers and exposed or not exposed to aircraft noise for 4 days. Proteomic analysis (using mass spectrometry) revealed a pro-inflammatory phenotype induced by noise exposure that was less pronounced in noise-exposed gp91phox−/y mice. Using in vivo fluorescence microscopy, we found a higher number of adhesive leukocytes in noise-exposed wild type mice. Dorsal microvascular diameter (by trend), red blood cell velocity, and segmental blood flow were also decreased by noise exposure indicating microvascular constriction. All adverse effects on functional parameters were normalized or improved at least by trend in noise-exposed gp91phox−/y mice. Noise exposure also induced endothelial dysfunction in cerebral microvessels, which was associated with higher oxidative stress burden and inflammation, as measured using video microscopy. We here establish a link between a pro-inflammatory phenotype of plasma, activation of circulating leukocytes and microvascular dysfunction in mice exposed to aircraft noise. The phagocytic NADPH oxidase was identified as a central player in the underlying pathophysiological mechanisms., Graphical abstract Image 1, Highlights • Noise exposure induces a pro-thrombo-inflammatory phenotype in mouse plasma. • Aircraft noise increases leukocyte-endothelium interactions in dorsal microvessels. • Noise decreases segmental blood flow/red blood cell velocity in dorsal microvessels. • Noise increases cerebral microvascular dysfunction and oxidative stress. • Nox2 deficiency (gp91phox-/y) improves noise-induced adverse effects.
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- 2021
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7. Regulation of NADPH oxidase-mediated superoxide production by acetylation and deacetylation
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Ning Xia, Stefan Tenzer, Oleg Lunov, Martin Karl, Thomas Simmet, Andreas Daiber, Thomas Münzel, Gisela Reifenberg, Ulrich Förstermann, and Huige Li
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Physiology ,resveratrol ,sirtuin 1 ,histone acetyltransferase ,Sirtuine ,chemistry.chemical_compound ,Histone deacetylases ,Sirtuin 1 ,Physiology (medical) ,NADPH-Oxidase ,medicine ,QP1-981 ,ddc:610 ,Original Research ,acetylation ,Acetyltransferasen ,NADPH oxidase ,biology ,Superoxide ,Acetylation ,Histone acetyltransferase ,Trichostatin A ,chemistry ,Biochemistry ,Histone acetyltransferases ,Resveratrol ,NADPH oxidases ,histone deacetylase ,biology.protein ,Histone deacetylase ,DDC 610 / Medicine & health ,Nicotinamide adenine dinucleotide phosphate ,Rac1 ,medicine.drug - Abstract
Oral treatment of apolipoprotein E-knockout (ApoE-KO) mice with the putative sirtuin 1 (SIRT1) activator resveratrol led to a reduction of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in the heart. In contrast, the SIRT1 inhibitor EX527 enhanced the superoxide production in isolated human polymorphonuclear granulocytes. In human monocytic THP-1 cells, phorbol ester-stimulated superoxide production was enhanced by inhibitors of histone deacetylases (HDACs; including quisinostat, trichostatin A (TSA), PCI34051, and tubastatin A) and decreased by inhibitors of histone acetyltransferases [such as garcinol, curcumin, and histone acetyltransferase (HAT) Inhibitor II]. These results indicate that protein acetylation and deacetylation may represent crucial mechanisms regulating NADPH oxidase-mediated superoxide production. In cell-free systems, incubation of recombinant Rac1 with SIRT1 resulted in decreased Rac1 acetylation. Mass spectrometry analyses identified lysine 166 (K166) in Rac1 as a residue targeted by SIRT1. Deacetylation of Rac1 by SIRT1 markedly reduced the interaction of Rac1 with p67phox in in vitro assays. Computational modeling analyses revealed that K166 deacetylation of Rac1 led to a 5-fold reduction in its binding affinity to guanosine-5'-triphosphate, and a 21-fold decrease in its binding potential to p67phox. The latter is crucial for Rac1-mediated recruitment of p67phox to the membrane and for p67phox activation. In conclusion, both SIRT1 and non-sirtuin deacetylases play a role in regulating NADPH oxidase activity. Rac1 can be directly deacetylated by SIRT1 in a cell-free system, leading to an inhibition of Rac1-p67phox interaction. The downstream targets of non-sirtuin deacetylases are still unknown. The in vivo significance of these findings needs to be investigated in future studies., publishedVersion
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- 2021
8. Inhibition of Rac1 GTPase Decreases Vascular Oxidative Stress, Improves Endothelial Function, and Attenuates Atherosclerosis Development in Mice
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Sebastian Zimmer, Philip Roger Goody, Matthias Oelze, Alexander Ghanem, Cornelius F. Mueller, Ulrich Laufs, Andreas Daiber, Felix Jansen, Georg Nickenig, and Sven Wassmann
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RHOA ,Inflammation ,Vascular permeability ,free radicals ,Pharmacology ,Cardiovascular Medicine ,medicine.disease_cause ,Actin cytoskeleton organization ,endothelial function ,medicine ,oxidative stress ,Diseases of the circulatory (Cardiovascular) system ,ddc:610 ,Endothelial dysfunction ,Original Research ,chemistry.chemical_classification ,Reactive oxygen species ,NADPH oxidase ,GTPases ,biology ,medicine.disease ,chemistry ,atherosclerosis, endothelial function, oxidative stress, free radicals, Rac1, GTPases ,RC666-701 ,biology.protein ,medicine.symptom ,atherosclerosis ,Cardiology and Cardiovascular Medicine ,Oxidative stress ,Rac1 - Abstract
Aims: Oxidative stress and inflammation contribute to atherogenesis. Rac1 GTPase regulates pro-oxidant NADPH oxidase activity, reactive oxygen species (ROS) formation, actin cytoskeleton organization and monocyte adhesion. We investigated the vascular effects of pharmacological inhibition of Rac1 GTPase in mice.Methods and Results: We treated wild-type and apolipoprotein E-deficient (ApoE−/−) mice with Clostridium sordellii lethal toxin (LT), a Rac1 inhibitor, and assessed vascular oxidative stress, expression and activity of involved proteins, endothelial function, macrophage infiltration, and atherosclerosis development. LT-treated wild-type mice displayed decreased vascular NADPH oxidase activity and ROS production. Therapeutic LT doses had no impact on behavior, food intake, body weight, heart rate, blood pressure, vascular and myocardial function, differential blood count, and vascular permeability. ApoE−/− mice were fed a cholesterol-rich diet and were treated with LT or vehicle. LT treatment led to decreased aortic Rac1 GTPase activity, NADPH oxidase activity and ROS production, but had no impact on expression and membrane translocation of NADPH oxidase subunits and RhoA GTPase activity. LT-treated mice showed improved aortic endothelium-dependent vasodilation, attenuated atherosclerotic lesion formation and reduced macrophage infiltration of atherosclerotic plaques. Concomitant treatment of cholesterol-fed ApoE−/− mice with LT, the specific synthetic Rac1 inhibitor NSC 23766 or simvastatin comparably reduced aortic Rac1 activity, NADPH oxidase activity, oxidative stress, endothelial dysfunction, atherosclerosis development, and macrophage infiltration.Conclusions: These findings identify an important role of the small GTPase Rac1 in atherogenesis and provide a potential target for anti-atherosclerotic therapy.
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- 2021
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9. GLP-1 Analog Liraglutide Improves Vascular Function in Polymicrobial Sepsis by Reduction of Oxidative Stress and Inflammation
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Konstantina Filippou, Swenja Kröller-Schön, Sanela Kalinovic, Andreas Daiber, Markus Bosmann, Franziska Aust, Simeon Tsohataridis, Johanna Helmstädter, Katie Frenis, Ksenija Vujacic-Mirski, Thomas Münzel, Matthias Oelze, Leonie Küster, Sebastian Steven, and Karin Keppeler
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0301 basic medicine ,Lipopolysaccharide ,Physiology ,glucagon-like peptide-1 (GLP-1) ,Clinical Biochemistry ,peritoneal and polymicrobial sepsis ,Inflammation ,RM1-950 ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease_cause ,Biochemistry ,Article ,endothelial dysfunction ,Sepsis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,oxidative stress ,vascular inflammation ,Endothelial dysfunction ,Interleukin 6 ,Molecular Biology ,liraglutide ,biology ,business.industry ,Septic shock ,Cell Biology ,bacterial infections and mycoses ,medicine.disease ,cecal ligation and puncture (CLP) ,Nitric oxide synthase ,030104 developmental biology ,chemistry ,biology.protein ,Therapeutics. Pharmacology ,medicine.symptom ,business ,Oxidative stress ,incretins - Abstract
Sepsis causes high mortality in the setting of septic shock. LEADER and other trials revealed cardioprotective and anti-inflammatory properties of glucagon-like peptide-1 (GLP-1) analogs like liraglutide (Lira). We previously demonstrated improved survival in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of GLP-1 degradation. Here we investigate the effects of Lira in the polymicrobial sepsis model of cecal ligation and puncture (CLP). C57BL/6J mice were intraperitoneally injected with Lira (200 µg/kg/d, 3 days) and sepsis induced by CLP after one day of GLP-1 analog treatment. Survival and body temperature were monitored. Aortic vascular function (isometric tension recording), protein expression (immunohistochemistry and dot blot) and gene expression (qRT-PCR) were determined. Endothelium-dependent relaxation in the aorta was impaired by CLP and correlated with markers of inflammation (e.g., interleukin 6 and inducible nitric oxide synthase) and oxidative stress (e.g., 3-nitrotyrosine) was higher in septic mice, all of which was almost completely normalized by Lira therapy. We demonstrate that the GLP-1 analog Lira ameliorates sepsis-induced endothelial dysfunction by the reduction of vascular inflammation and oxidative stress. Accordingly, the findings suggest that the antioxidant and anti-inflammatory effects of GLP-1 analogs may be a valuable tool to protect the cardiovascular system from dysbalanced inflammation in polymicrobial sepsis.
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- 2021
10. Short-term e-cigarette vapour exposure causes vascular oxidative stress and dysfunction: evidence for a close connection to brain damage and a key role of the phagocytic NADPH oxidase (NOX-2)
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Marin Kuntic, Konstantina Filippou, John F. Keaney, Regina Huesmann, Thorsten Hoffmann, Andreas Daiber, Paul Stamm, Katie Frenis, Miroslava Kvandova, Maria Teresa Bayo Jimenez, Vivienne Brückl, Ksenija Vujacic-Mirski, Franco Varveri, Frank P. Schmidt, Matthias Oelze, Swenja Kröller-Schön, Omar Hahad, Steffen Daub, Sebastian Steven, Ahmad Al Zuabi, Tommaso Gori, Sanela Kalinovic, and Thomas Münzel
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Behavioural risk factor ,Inflammation ,Electronic Nicotine Delivery Systems ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease_cause ,Vascular Medicine ,Lifestyle drug ,Nicotine ,Lipid peroxidation ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Basic Science ,Animals ,Humans ,Medicine ,Endothelial dysfunction ,030212 general & internal medicine ,Macitentan ,NADPH oxidase ,biology ,business.industry ,Brain ,NADPH Oxidases ,medicine.disease ,E-cigarette vapour ,Editor's Choice ,Leukemia, Myeloid, Acute ,Oxidative Stress ,medicine.anatomical_structure ,chemistry ,E-Cigarette Vapor ,NADPH Oxidase 2 ,Neoplastic Stem Cells ,biology.protein ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Oxidative stress ,medicine.drug ,Blood vessel - Abstract
Aims Electronic (e)-cigarettes have been marketed as a ‘healthy’ alternative to traditional combustible cigarettes and as an effective method of smoking cessation. There are, however, a paucity of data to support these claims. In fact, e-cigarettes are implicated in endothelial dysfunction and oxidative stress in the vasculature and the lungs. The mechanisms underlying these side effects remain unclear. Here, we investigated the effects of e-cigarette vapour on vascular function in smokers and experimental animals to determine the underlying mechanisms. Methods and results Acute e-cigarette smoking produced a marked impairment of endothelial function in chronic smokers determined by flow-mediated dilation. In mice, e-cigarette vapour without nicotine had more detrimental effects on endothelial function, markers of oxidative stress, inflammation, and lipid peroxidation than vapour containing nicotine. These effects of e-cigarette vapour were largely absent in mice lacking phagocytic NADPH oxidase (NOX-2) or upon treatment with the endothelin receptor blocker macitentan or the FOXO3 activator bepridil. We also established that the e-cigarette product acrolein, a reactive aldehyde, recapitulated many of the NOX-2-dependent effects of e-cigarette vapour using in vitro blood vessel incubation. Conclusions E-cigarette vapour exposure increases vascular, cerebral, and pulmonary oxidative stress via a NOX-2-dependent mechanism. Our study identifies the toxic aldehyde acrolein as a key mediator of the observed adverse vascular consequences. Thus, e-cigarettes have the potential to induce marked adverse cardiovascular, pulmonary, and cerebrovascular consequences. Since e-cigarette use is increasing, particularly amongst youth, our data suggest that aggressive steps are warranted to limit their health risks.
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- 2019
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11. The roles of gut microbiota and circadian rhythm in the cardiovascular protective effects of polyphenols
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Andreas Daiber, Ning Xia, Andy W C Man, and Huige Li
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0301 basic medicine ,Circadian clock ,610 Medizin ,Review Article ,Gut flora ,Health benefits ,Bioinformatics ,Themed Section: Review Articles ,03 medical and health sciences ,0302 clinical medicine ,Nutraceutical ,610 Medical sciences ,Medicine ,Circadian rhythm ,Pharmacology ,biology ,business.industry ,Polyphenols ,food and beverages ,biology.organism_classification ,Circadian Rhythm ,Diet ,Gastrointestinal Microbiome ,030104 developmental biology ,Polyphenol ,Dietary Supplements ,business ,030217 neurology & neurosurgery - Abstract
Polyphenols are secondary metabolites of plants that have been widely studied for their health benefits as antioxidants. In the last decade, several clinical trials and epidemiological studies have shown that long-term consumption of polyphenol-rich diet protects against chronic diseases such as cancers and cardiovascular diseases. Current cardiovascular studies have also suggested an important role of gut microbiota and circadian rhythm in the pathogenesis metabolic and cardiovascular diseases. It is known that polyphenols can modulate the composition of core gut microbiota and interact with circadian clocks. In this article, we summarize recent findings, review the molecular mechanisms and the potential of polyphenols as dietary supplements for regulating gut microbiota and circadian rhythms, and discuss future research directions. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc.
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- 2019
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12. Chronic occupational noise exposure: Effects on DNA damage, blood pressure, and serum biochemistry
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Majid Bagheri Hosseinabadi, Andreas Daiber, Narges Khanjani, Mohammad Yaghmorloo, and Thomas Münzel
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Adult ,Male ,Serum ,0301 basic medicine ,DNA damage ,Health, Toxicology and Mutagenesis ,Physiology ,Blood Pressure ,Iran ,010501 environmental sciences ,medicine.disease_cause ,01 natural sciences ,Peripheral blood mononuclear cell ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,Occupational Exposure ,Genetics ,medicine ,Humans ,Industry ,0105 earth and related environmental sciences ,chemistry.chemical_classification ,Glutathione Peroxidase ,biology ,business.industry ,Glutathione peroxidase ,Ceruloplasmin ,Glutathione ,Middle Aged ,Comet assay ,030104 developmental biology ,Blood pressure ,chemistry ,Leukocytes, Mononuclear ,Noise, Occupational ,biology.protein ,Comet Assay ,business ,Oxidative stress ,DNA Damage - Abstract
Noise levels experienced by industrial workers may cause both auditory and non-auditory harmful effects. We have studied the effects of chronic industrial noise exposure on DNA damage, blood pressure, and serum biochemistry in factory workers. Male workers (109 individuals) in three parts of a food factory in Shahroud, Iran were enrolled as the exposed group and male office workers (123 individuals) were the unexposed control group. Noise exposure was measured (dosimetry) and the comet assay was used to evaluate DNA damage in peripheral blood mononuclear cells. Glutathione peroxidase (GPx) and ceruloplasmin (Cp) levels were measured in serum samples. GPx levels, systolic and diastolic blood pressure, and DNA damage were significantly higher in the exposed group than in the control group. However, ceruloplasmin levels were not significantly different. Based on multivariate linear regression analysis, noise exposure was the most important predictor of GPx levels, systolic and diastolic blood pressure, and DNA damage.
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- 2019
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13. Out of Your Mind!? Embodied Interaction in Sports
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Rakesh Patibanda, Wanyu Liu, Vincent van Rheden, Elise van den Hoven, Thomas Grah, Florian 'Floyd' Mueller, Florian Daiber, and Alexander Meschtscherjakov
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biology ,Athletes ,media_common.quotation_subject ,05 social sciences ,Perspective (graphical) ,ComputingMilieux_PERSONALCOMPUTING ,ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION ,020207 software engineering ,Muscle memory ,02 engineering and technology ,Interaction design ,biology.organism_classification ,Adventure ,1202 Building, 1503 Business and Management ,Feeling ,Embodied cognition ,Aesthetics ,ComputerApplications_MISCELLANEOUS ,Realm ,0202 electrical engineering, electronic engineering, information engineering ,0501 psychology and cognitive sciences ,Psychology ,050107 human factors ,media_common - Abstract
People engage in sportive activities for reasons beyond improving their athletic performance. They also seek experiences like fun, adventure, a feeling of oneness, clear their heads, and flow. Since sport is a highly bodily experience, we argue that taking an embodied interaction perspective to inspire interaction design of sports systems is a promising direction in HCI research and practice. This workshop will address the challenges of designing interactive systems in the realm of sports from an embodied interaction perspective focusing on athletes' experience rather than performance. We will explore how interactive systems enhance sports experience without distracting from the actual goal of the athlete, such as freeing the mind. We will focus on several topics of interest such as sensory augmentation, augmented experience, multi-modal interaction, and motor learning in sports.
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- 2021
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14. Ablation of lysozyme M-positive cells prevents aircraft noise-induced vascular damage without improving cerebral side effects
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Philip Wenzel, Clemens Sommer, Eva Schramm, Ari Waisman, Katrin Frauenknecht, Sebastian Steven, Thomas Münzel, Sanela Kalinovic, Katie Frenis, Adrian Gericke, Johanna Helmstädter, Swenja Kröller-Schön, Yue Ruan, Matthias Oelze, Maria Teresa Bayo Jimenez, Omar Hahad, Subao Jiang, and Andreas Daiber
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Male ,Environmental risk factor ,Myeloid ,Aircraft ,Physiology ,610 Medizin ,medicine.disease_cause ,610 Medical sciences ,Myeloid Cells ,Endothelial dysfunction ,Aircraft noise exposure ,Peripheral Vascular Diseases ,NADPH oxidase ,biology ,Microglia ,Chemistry ,Brain ,Arteries ,Original Contribution ,medicine.anatomical_structure ,Integrin alpha M ,Noise, Transportation ,Cerebral inflammation ,Encephalitis ,medicine.symptom ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,Inflammation ,Mice, Transgenic ,Physiology (medical) ,Internal medicine ,medicine.artery ,medicine ,Animals ,Aorta ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,Endocrinology ,biology.protein ,Muramidase ,Diphtheria toxin ,Reactive Oxygen Species ,Oxidative stress ,Gene Deletion ,Myeloid cell ablation - Abstract
Aircraft noise induces vascular and cerebral inflammation and oxidative stress causing hypertension and cardiovascular/cerebral dysfunction. With the present studies, we sought to determine the role of myeloid cells in the vascular vs. cerebral consequences of exposure to aircraft noise. Toxin-mediated ablation of lysozyme M+ (LysM+) myeloid cells was performed in LysMCreiDTR mice carrying a cre-inducible diphtheria toxin receptor. In the last 4d of toxin treatment, the animals were exposed to noise at maximum and mean sound pressure levels of 85 and 72 dB(A), respectively. Flow cytometry analysis revealed accumulation of CD45+, CD11b+, F4/80+, and Ly6G−Ly6C+ cells in the aortas of noise-exposed mice, which was prevented by LysM+ cell ablation in the periphery, whereas brain infiltrates were even exacerbated upon ablation. Aircraft noise-induced increases in blood pressure and endothelial dysfunction of the aorta and retinal/mesenteric arterioles were almost completely normalized by ablation. Correspondingly, reactive oxygen species in the aorta, heart, and retinal/mesenteric vessels were attenuated in ablated noise-exposed mice, while microglial activation and abundance in the brain was greatly increased. Expression of phagocytic NADPH oxidase (NOX-2) and vascular cell adhesion molecule-1 (VCAM-1) mRNA in the aorta was reduced, while NFκB signaling appeared to be activated in the brain upon ablation. In sum, we show dissociation of cerebral and peripheral inflammatory reactions in response to aircraft noise after LysM+ cell ablation, wherein peripheral myeloid inflammatory cells represent a dominant part of the pathomechanism for noise stress-induced cardiovascular effects and their central nervous counterparts, microglia, as key mediators in stress responses.
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- 2020
15. Tissue factor cytoplasmic tail regulates myeloid cell derived superoxide formation and TGF-beta 1 driven cardiac remodeling in myocardial infarction
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Jeremy Lagrange, Philip Wenzel, Michael Molitor, Wolfram Ruf, T Gori, Hendrik Milting, Johannes Wild, Sabine Kossmann, Ksenija Vujacic-Mirski, Thomas Muenzel, Venkata Garlapati, Susanne Karbach, Panagiotis Efentakis, Moritz Brandt, and Andreas Daiber
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Myeloid ,biology ,Superoxide ,business.industry ,Cell ,medicine.disease ,chemistry.chemical_compound ,Tissue factor ,medicine.anatomical_structure ,chemistry ,Cytoplasm ,biology.protein ,medicine ,Cancer research ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,TGF beta 1 - Abstract
Background In the setting of myocardial infarction (MI), patients with coronary no-reflow and/or delayed presentation after onset of symptoms (sub-acute MI) are inflicted by severe thrombo-inflammation and are marked by worse clinical outcome. However, it is unclear whether tissue factor (TF) contributes to outcome post MI solely by the regulatory functions of its cytoplasmic tail independently of its coagulation activity. Purpose We analyzed the role of the TF cytoplasmic domain in the recruitment of myeloid cells into the infarcted myocardium and the consequences on cardiac remodeling, scar formation, development of heart failure and survival post MI. Methods Twelve Patients enrolled in the MICAT (Mainzer Intracoronary Database, ClinicalTrials.gov Identifier: NCT02180178) study were examined. Patients with sub-acute MI and stable coronary artery disease were defined and monocytes were isolated from peripheral blood mononuclear cells (PBMCs). Human heart samples acquired from the left ventricular wall of explanted hearts following cardiac transplantation or obtained during implantation of left ventricular assist device. Samples were investigated for downstream analysis of protein by western blots, RNA quantification and cryo-sectioning. MI was induced in 9 to 12 weeks old male C57BL/6J mice, mice specifically lacking the cytoplasmic tail (CT) of TF (TFΔCT mice) and TFfl/flLysMCre+/− mice by permanent ligation of the left anterior descending artery. Left ventricular function was assessed by High-Frequency Ultrasound System. Infiltration of immune cells into the infarcted myocardium was analyzed by performing flow cytometric analysis after enzymatic digestion of the myocardium. Superoxide levels were quantified by HPLC-based measurement of dihydroethidium derived oxidation product 2-hydroxy ethidium. Results Circulating monocytes in patients with sub-acute MI showed increased nitrosative stress as well as increased phosphorylation of TF CT along with TGF-β1 and NF-kB inflammatory activation, which was recapitulated in cardiac tissue of end-stage heart failure patients with chronic MI. MI results in phosphorylation of the CT of TF within myeloid cells. Using mice with conditional knockout of TF on myeloid cells or TFΔCT mice, we found that this regulatory intracellular domain of TF within myeloid cells is required for cardiac infiltration of inflammatory Ly6Chigh TF+ monocytes, Rac-1 GTPase and superoxide formation of gp91phox + myeloid cells in MI. TGF-β1 dependent SMAD2 activation and cardiac collagen deposition as late sequel of MI was reduced in TFΔCT mice, resulting in attenuated cardiac dysfunction and reduced mortality. Conclusion We conclude that, TF CT drives NADPH-oxidase derived superoxide formation, thrombo-inflammation and cardiac fibrosis. Therefore, it might serve as putative biomarker and risk predictor in MI Funding Acknowledgement Type of funding source: None
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- 2020
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16. Germ-free housing conditions do not affect aortic root and aortic arch lesion size of late atherosclerotic low-density lipoprotein receptor-deficient mice
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Thomas Koeck, Philipp S. Wild, Giulia Pontarollo, Sven Jäckel, Christian Weber, Yvonne Jansen, Cornelia Karwot, Yvonne Döring, Wolfram Ruf, Emiel P. C. van der Vorst, Andreas Daiber, Klytaimnistra Kiouptsi, Christoph Reinhardt, Susanne Gerber, Johannes Braun, Angelica Karpi, Hristo Todorov, Franziska Bayer, Pathologie, and RS: Carim - B07 The vulnerable plaque: makers and markers
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0301 basic medicine ,Aortic arch ,Male ,Pathology ,aortic root ,Aortic root ,aortic arch ,Functional impact ,Aorta, Thoracic ,HYPERCHOLESTEROLEMIA ,Mice ,0302 clinical medicine ,Deficient mouse ,610 Medicine & health ,Mice, Knockout ,BILE-ACIDS ,Cellular composition ,Microbiota ,CHOLESTEROL ,GUT MICROBIOTA ,Gastroenterology ,inflammatory markers ,Housing, Animal ,Plaque, Atherosclerotic ,macrophages ,smooth muscle cells ,Infectious Diseases ,germ-free ,030211 gastroenterology & hepatology ,Female ,lipids (amino acids, peptides, and proteins) ,SEX ,TRIMETHYLAMINE ,medicine.symptom ,Microbiology (medical) ,medicine.medical_specialty ,Biology ,METABOLISM ,lesion size ,Microbiology ,Lesion ,03 medical and health sciences ,INFLAMMATION ,medicine.artery ,medicine ,Animals ,Germ-Free Life ,Humans ,lcsh:RC799-869 ,Addendum ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Receptors, LDL ,low-density lipoprotein receptor-deficient mouse ,age ,LDL receptor ,lcsh:Diseases of the digestive system. Gastroenterology ,atherosclerosis - Abstract
The microbiota has been linked to the development of atherosclerosis, but the functional impact of these resident bacteria on the lesion size and cellular composition of atherosclerotic plaques in the aorta has never been experimentally addressed with the germ-free low-density lipoprotein receptor-deficient (Ldlr(-/-)) mouse atherosclerosis model. Here, we report that 16 weeks of high-fat diet (HFD) feeding of hypercholesterolemicLdlr(-/-)mice at germ-free (GF) housing conditions did not impact relative aortic root plaque size, macrophage content, and necrotic core area. Likewise, we did not find changes in the relative aortic arch lesion size. However, late atherosclerotic GFLdlr(-/-)mice had altered inflammatory plasma protein markers and reduced smooth muscle cell content in their atherosclerotic root plaques relative to CONV-RLdlr(-/-)mice. Neither absolute nor relative aortic root or aortic arch plaque size correlated with age. Our analyses on GFLdlr(-/-)mice did not reveal a significant contribution of the microbiota in late aortic atherosclerosis.
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- 2020
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17. Vascular and Cardiac Oxidative Stress and Inflammation as Targets for Cardioprotection
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Sebastian Steven, Gerhild Euler, Andreas Daiber, and Rainer Schulz
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Inflammation ,Bioinformatics ,medicine.disease_cause ,Antioxidants ,Drug Discovery ,medicine ,Humans ,Myocardial infarction ,Pharmacology ,chemistry.chemical_classification ,Cardioprotection ,Reactive oxygen species ,Ischemic cardiomyopathy ,biology ,business.industry ,Angiotensin-converting enzyme ,medicine.disease ,Crosstalk (biology) ,Oxidative Stress ,chemistry ,biology.protein ,medicine.symptom ,business ,Reactive Oxygen Species ,Oxidation-Reduction ,Oxidative stress - Abstract
Cardiac and vascular diseases are often associated with increased oxidative stress and inflammation, and both may contribute to the disease progression. However, successful applications of antioxidants in the clinical setting are very rare and specific anti-inflammatory therapeutics only emerged recently. Reasons for this rely on the great diversity of oxidative stress and inflammatory cells that can either act as cardioprotective or cause tissue damage in the heart. Recent large-scale clinical trials found that highly specific anti-inflammatory therapies using monoclonal antibodies against cytokines resulted in lower cardiovascular mortality in patients with pre-existing atherosclerotic disease. In addition, unspecific antiinflammatory medication and established cardiovascular drugs with pleiotropic immunomodulatory properties such as angiotensin converting enzyme (ACE) inhibitors or statins have proven beneficial cardiovascular effects. Normalization of oxidative stress seems to be a common feature of these therapies, which can be explained by a close interaction/crosstalk of the cellular redox state and inflammatory processes. In this review, we give an overview of cardiac reactive oxygen species (ROS) sources and processes of cardiac inflammation as well as the connection of ROS and inflammation in ischemic cardiomyopathy in order to shed light on possible cardioprotective interventions.
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- 2020
18. Conserved and divergent aspects of Robo receptor signaling and regulation betweenDrosophilaRobo1 andC. elegansSAX-3
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Timothy A. Evans, Trent Daiber, Greg J. Bashaw, and Christine J. VanderZwan-Butler
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Developmental and Behavioral Genetics ,AcademicSubjects/SCI01140 ,animal structures ,AcademicSubjects/SCI00010 ,Nerve Tissue Proteins ,Endosomes ,Robo ,AcademicSubjects/SCI01180 ,Conserved sequence ,Evolution, Molecular ,03 medical and health sciences ,0302 clinical medicine ,Slit ,ROBO1 ,Genetics ,Animals ,Drosophila Proteins ,SAX-3 ,Receptors, Immunologic ,Drosophila (subgenus) ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,Conserved Sequence ,midline crossing ,030304 developmental biology ,Neurons ,Investigation ,0303 health sciences ,biology ,axon guidance ,Genetic Complementation Test ,fungi ,Membrane Proteins ,biology.organism_classification ,Cell biology ,Protein Transport ,Drosophila melanogaster ,Ectodomain ,Roundabout ,AcademicSubjects/SCI00960 ,Axon guidance ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
The evolutionarily conserved Roundabout (Robo) family of axon guidance receptors control midline crossing of axons in response to the midline repellant ligand Slit in bilaterian animals including insects, nematodes, and vertebrates. Despite this strong evolutionary conservation, it is unclear whether the signaling mechanism(s) downstream of Robo receptors are similarly conserved. To directly compare midline repulsive signaling in Robo family members from different species, here we use a transgenic approach to express the Robo family receptor SAX-3 from the nematodeCaenorhabditis elegansin neurons of the fruit fly,Drosophila melanogaster. We examine SAX-3’s ability to repelDrosophilaaxons from the Slit-expressing midline in gain of function assays, and test SAX-3’s ability to substitute forDrosophilaRobo1 during fly embryonic development in genetic rescue experiments. We show thatC. elegansSAX-3 is properly translated and localized to neuronal axons when expressed in theDrosophilaembryonic CNS, and that SAX-3 can signal midline repulsion inDrosophilaembryonic neurons, although not as efficiently asDrosophilaRobo1. Using a series of Robo1/SAX-3 chimeras, we show that the SAX-3 cytoplasmic domain can signal midline repulsion to the same extent as Robo1 when combined with the Robo1 ectodomain. We show that SAX-3 is not subject to endosomal sorting by the negative regulator Commissureless (Comm) inDrosophilaneuronsin vivo, and that peri-membrane and ectodomain sequences are both required for Comm sorting ofDrosophilaRobo1.
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- 2020
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19. Novel Concept for the Regulation of eNOS (Endothelial Nitric Oxide Synthase) Activity: Inhibitory Effects of the Enigma Homolog Protein and the PHLPP (Pleckstrin Homology Domain and Leucine-Rich Repeat Protein Phosphatase)-2 on Akt (Protein Kinase B)-Dependent Nitric Oxide Synthase Activation
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Thomas Münzel and Andreas Daiber
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PHLPP ,biology ,Nitric Oxide Synthase Type III ,Kinase ,Proteins ,Pleckstrin Homology Domains ,Protein phosphatase 2 ,Leucine-rich repeat ,Vascular Remodeling ,Leucine-Rich Repeat Proteins ,Cell biology ,Nitric oxide ,Pleckstrin homology domain ,Nitric oxide synthase ,chemistry.chemical_compound ,chemistry ,biology.protein ,Phosphoprotein Phosphatases ,Humans ,Protein Phosphatase 2 ,Nitric Oxide Synthase ,Cardiology and Cardiovascular Medicine ,Protein kinase B ,Proto-Oncogene Proteins c-akt - Published
- 2020
20. Oxidative stress and inflammation contribute to traffic noise-induced vascular and cerebral dysfunction via uncoupling of nitric oxide synthases
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Andreas Daiber, Swenja Kröller-Schön, Thomas Münzel, Huige Li, Matthias Oelze, Omar Hahad, Sebastian Steven, and Rainer Schulz
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0301 basic medicine ,Sympathetic nervous system ,Clinical Biochemistry ,Environmental pollution ,medicine.disease_cause ,Biochemistry ,chemistry.chemical_compound ,0302 clinical medicine ,RAAS, renin-angiotensin-aldosterone system ,Enos ,Risk Factors ,NOS, nitric oxide synthase ,lcsh:QH301-705.5 ,chemistry.chemical_classification ,lcsh:R5-920 ,biology ,Cardiovascular disease ,NOX, NADPH oxidase ,medicine.anatomical_structure ,Noise, Transportation ,medicine.symptom ,lcsh:Medicine (General) ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Articles from the Special Issue on Impact of environmental pollution and stress on redox signaling and oxidative stress pathways ,Edited by Thomas Münzel and Andreas Daiber ,l-NAME, L-NG-nitro-arginine methyl ester ,Inflammation ,Nitric Oxide ,Nitric oxide ,03 medical and health sciences ,ROS, reactive oxygen species ,Internal medicine ,SOD, superoxide dismutase ,PKC, protein kinase C ,medicine ,Humans ,Environmental risk factors ,Reactive oxygen species ,HPA, hypothalamic-pituitary-adrenal ,business.industry ,Traffic noise exposure ,Organic Chemistry ,BH4, tetrahydrobiopterin ,NOS uncoupling ,biology.organism_classification ,IL, interleukin ,Sleep deprivation ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,chemistry ,lcsh:Biology (General) ,business ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
Environmental pollution and non-chemical stressors such as mental stress or traffic noise exposure are increasingly accepted as health risk factors with substantial contribution to chronic noncommunicable diseases (e.g. cardiovascular, metabolic and mental). Whereas the mechanisms of air pollution-mediated adverse health effects are well characterized, the mechanisms of traffic noise exposure are not completely understood, despite convincing clinical and epidemiological evidence for a significant contribution of environmental noise to overall mortality and disability. The initial mechanism of noise-induced cardiovascular, metabolic and mental disease is well defined by the „noise reaction model“ and consists of neuronal activation involving the hypothalamic-pituitary-adrenal (HPA) axis as well as the sympathetic nervous system, followed by a classical stress response via cortisol and catecholamines. Stress pathways are initiated by noise-induced annoyance and sleep deprivation/fragmentation. This review highlights the down-stream pathophysiology of noise-induced mental stress, which is based on an induction of inflammation and oxidative stress. We highlight the sources of reactive oxygen species (ROS) involved and the known targets for noise-induced oxidative damage. Part of the review emphasizes noise-triggered uncoupling/dysregulation of endothelial and neuronal nitric oxide synthase (eNOS and nNOS) and its central role for vascular dysfunction., Graphical abstract Image 1, Highlights • Exposure to (traffic) noise causes non-auditory (indirect) cardiovascular and cerebral health harms via neuronal activation. • Noise activates the HPA axis and sympathetic nervous system increasing levels of stress hormones, vasoconstrictors and ROS. • Noise induces inflammation and stimulates several ROS sources leading to cerebral and cardiovascular oxidative damage. • Noise leads to eNOS and nNOS uncoupling contributing to cardiometabolic disease and cognitive impairment.
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- 2020
21. The Jungle Warm-Up Run
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Antonio Krüger, Florian Daiber, Frederik Wiehr, and Marko Vujic
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biology ,Relative intensity ,Sequential game ,Athletes ,05 social sciences ,Applied psychology ,ComputingMilieux_PERSONALCOMPUTING ,020207 software engineering ,02 engineering and technology ,biology.organism_classification ,Augmented sports ,0202 electrical engineering, electronic engineering, information engineering ,Jungle ,0501 psychology and cognitive sciences ,Duration (project management) ,Psychology ,Warming up ,050107 human factors ,Avatar - Abstract
In virtually all sports, warming up is considered important to physically and mentally prepare an athlete for intensive efforts. General warm-up procedures with a correct technique for exercises are widely accepted to prevent injuries. However, most athletes do not warm up at all, or they do not follow a correct procedure. To address this, we designed and evaluated an exergame for warm-up guidance in a user-centered design process involving a fitness expert. The game augments the athlete with coach-guided dynamic game elements. With an online survey (N=466), we investigated general warm-up habits and provide insights on design game elements in this domain. In a between-subject user study (N=12), we compared our proposed exergame against a classic video instructor. As a result of using the exergame, the participants were more engaged (i.e. longer warm-up duration, higher relative intensity, more enjoyment) while reporting the same level of exertion.
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- 2020
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22. Regulation of vascular function and inflammation via cross talk of reactive oxygen and nitrogen species from mitochondria or nadph oxidase—implications for diabetes progression
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Thomas Münzel, Sebastian Steven, Ksenija Vujacic-Mirski, Matthias Oelze, Fabio Di Lisa, Andreas Daiber, and Sanela Kalinovic
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0301 basic medicine ,Antioxidant ,medicine.medical_treatment ,Review ,030204 cardiovascular system & hematology ,Mitochondrion ,medicine.disease_cause ,lcsh:Chemistry ,0302 clinical medicine ,Endothelial dysfunction ,lcsh:QH301-705.5 ,Spectroscopy ,NADPH oxidase ,biology ,Chemistry ,General Medicine ,Reactive Nitrogen Species ,Computer Science Applications ,Cell biology ,Mitochondria ,Cardiovascular Diseases ,Disease Progression ,medicine.symptom ,Inflammation ,ENOS uncoupling ,Oxidative phosphorylation ,Kindling radicals ,Low-grade inflammation ,Oxidative stress ,Redox cross talk ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,medicine ,Diabetes Mellitus ,Animals ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,Organic Chemistry ,NADPH Oxidases ,medicine.disease ,Angiotensin II ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,biology.protein ,Reactive Oxygen Species - Abstract
Oxidative stress plays a key role for the development of cardiovascular, metabolic, and neurodegenerative disease. This concept has been proven by using the approach of genetic deletion of reactive oxygen and nitrogen species (RONS) producing, pro-oxidant enzymes as well as by the overexpression of RONS detoxifying, antioxidant enzymes leading to an amelioration of the severity of diseases. Vice versa, the development and progression of cardiovascular diseases is aggravated by overexpression of RONS producing enzymes as well as deletion of RONS detoxifying enzymes. We have previously identified cross talk mechanisms between different sources of RONS, which can amplify the oxidative stress-mediated damage. Here, the pathways and potential mechanisms leading to this cross talk are analyzed in detail and highlighted by selected examples from the current literature and own data including hypoxia, angiotensin II (AT-II)-induced hypertension, nitrate tolerance, aging, and others. The general concept of redox-based activation of RONS sources via “kindling radicals” and enzyme-specific “redox switches” as well as the interaction with redox-sensitive inflammatory pathways are discussed. Here, we present evidence for the existence of such cross talk mechanisms in the setting of diabetes and critically assess their contribution to the severity of diabetic complications.
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- 2020
23. Development of an Analytical Assay for Electrochemical Detection and Quantification of Protein-Bound 3-Nitrotyrosine in Biological Samples and Comparison with Classical, Antibody-Based Methods
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Bato Korac, Matthias Oelze, Andreas Daiber, Ksenija Vujacic-Mirski, Thomas Münzel, Kai Bruns, Sanela Kalinovic, Miloš Mojović, Sebastian Steven, and Swenja Kröller-Schön
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0301 basic medicine ,Physiology ,Clinical Biochemistry ,Dot blot ,mitochondrial superoxide ,Pronase ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Biochemistry ,High-performance liquid chromatography ,Article ,peroxynitrite ,Peroxynitrite ,03 medical and health sciences ,0302 clinical medicine ,Protein-bound 3-nitrotyrosine ,medicine ,oxidative stress ,Bovine serum albumin ,Molecular Biology ,chemistry.chemical_classification ,Detection limit ,Reactive oxygen species ,Chromatography ,HPLC with electrochemical detection ,biology ,lcsh:RM1-950 ,Cell Biology ,3. Good health ,030104 developmental biology ,lcsh:Therapeutics. Pharmacology ,chemistry ,Oxidative stress ,biology.protein ,protein-bound 3-nitrotyrosine ,Ex vivo ,Mitochondrial superoxide - Abstract
Reactive oxygen and nitrogen species (RONS) cause oxidative damage, which is associated with endothelial dysfunction and cardiovascular disease, but may also contribute to redox signaling. Therefore, their precise detection is important for the evaluation of disease mechanisms. Here, we compared three different methods for the detection of 3-nitrotyrosine (3-NT), a marker of nitro-oxidative stress, in biological samples. Nitrated proteins were generated by incubation with peroxynitrite or 3-morpholino sydnonimine (Sin-1) and subjected to total hydrolysis using pronase, a mixture of different proteases. The 3-NT was then separated by high performance liquid chromatography (HPLC) and quantified by electrochemical detection (ECD, CoulArray) and compared to classical methods, namely enzyme-linked immunosorbent assay (ELISA) and dot blot analysis using specific 3-NT antibodies. Calibration curves for authentic 3-NT (detection limit 10 nM) and a concentration-response pattern for 3-NT obtained from digested nitrated bovine serum albumin (BSA) were highly linear over a wide 3-NT concentration range. Also, ex vivo nitration of protein from heart, isolated mitochondria, and serum/plasma could be quantified using the HPLC/ECD method and was confirmed by LC-MS/MS. Of note, nitro-oxidative damage of mitochondria results in increased superoxide (O2&bull, &ndash, ) formation rates (measured by dihydroethidium-based HPLC assay), pointing to a self-amplification mechanism of oxidative stress. Based on our ex vivo data, the CoulArray quantification method for 3-NT seems to have some advantages regarding sensitivity and selectivity. Establishing a reliable automated HPLC assay for the routine quantification of 3-NT in biological samples of cell culture, of animal and human origin seems to be more sophisticated than expected.
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- 2020
24. Evaluating the efficacy of a preharvest combination of calcium and boron as foliar application to reduce sunburn on ‘Cripps Pink’ apples
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E. Lötze, S. Daiber, and S.J.E. Midgley
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0106 biological sciences ,biology ,chemistry.chemical_element ,Cripps Pink ,04 agricultural and veterinary sciences ,Horticulture ,Calcium ,biology.organism_classification ,medicine.disease ,01 natural sciences ,chemistry ,040103 agronomy & agriculture ,medicine ,0401 agriculture, forestry, and fisheries ,Preharvest ,Sunburn ,Boron ,010606 plant biology & botany - Published
- 2018
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25. α1AMPK deletion in myelomonocytic cells induces a pro-inflammatory phenotype and enhances angiotensin II-induced vascular dysfunction
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Marc Foretz, Moritz Brandt, Eberhard Schulz, Philip Wenzel, Matthias Oelze, John F. Keaney, Swenja Kröller-Schön, Thomas Münzel, Benoit Viollet, Thomas Jansen, Andreas Daiber, Sebastian Steven, Jeremy Lagrange, Miroslava Kvandova, Sanela Kalinovic, Tanja Schönfelder, Johannes Gutenberg - Universität Mainz (JGU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), and Johannes Gutenberg - University of Mainz (JGU)
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MESH: Signal Transduction ,0301 basic medicine ,CCR2 ,Physiology ,medicine.medical_treatment ,MESH: Aortic Diseases ,AMP-Activated Protein Kinases ,030204 cardiovascular system & hematology ,MESH: Mice, Knockout ,0302 clinical medicine ,MESH: Animals ,MESH: AMP-Activated Protein Kinases ,Aorta ,Cells, Cultured ,Mice, Knockout ,MESH: Cytokines ,MESH: Oxidative Stress ,biology ,Chemistry ,Angiotensin II ,MESH: Genetic Predisposition to Disease ,MESH: Aorta ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,Respiratory burst ,Vasodilation ,Phenotype ,Cytokine ,Cytokines ,Tumor necrosis factor alpha ,MESH: Angiotensin II ,Inflammation Mediators ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Signal Transduction ,MESH: Cells, Cultured ,MESH: Inflammation Mediators ,Aortic Diseases ,Inflammation ,MESH: Phenotype ,MESH: Vasodilation ,03 medical and health sciences ,Immune system ,MESH: Mice, Inbred C57BL ,Physiology (medical) ,medicine ,Animals ,Genetic Predisposition to Disease ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Interleukin 6 ,Macrophages ,MESH: Macrophages ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,MESH: Gene Deletion ,Cancer research ,biology.protein ,MESH: Disease Models, Animal ,Gene Deletion - Abstract
Aims Immune cell function involves energy-dependent processes including growth, proliferation, and cytokine production. Since the AMP-activated protein kinase (AMPK) is a crucial regulator of intracellular energy homeostasis, its expression and activity may also affect innate and adaptive immune cell responses. Therefore, we aimed to investigate the consequences of α1AMPK deletion in myelomonocytic cells on vascular function, inflammation, and hypertension during chronic angiotensin II (ATII) treatment. Methods and results We generated a mouse strain with α1AMPK deletion in lysozyme M+ myelomonocytic cells. Compared to controls, chronic ATII infusion (1 mg/kg/day for 7 days) lead to increased vascular oxidative stress and aggravated endothelial dysfunction in LysM-Cre+ x α1AMPKfl/fl mice. This was accompanied by an increased aortic infiltration of CD11b+F4/80+ macrophages and enhanced pro-inflammatory cytokine release (tumour necrosis factor-alpha, interferon-gamma, and interleukin-6). Mechanistically, we found that increased expression of C-C chemokine receptor 2 (CCR2) in α1AMPK deficient myelomonocytic cells facilitated their recruitment to the vascular wall. In addition, expression of the ATII receptor type 1a and the oxidative burst was increased in these cells, indicating an increased susceptibility towards pro-oxidant stimuli. Conclusions In summary, α1AMPK deletion in myelomonocytic cells aggravates vascular oxidative stress and dysfunction by enhancing their recruitment to the vascular wall and increasing their susceptibility towards pro-oxidant stimuli. Our observations suggest that metabolic control in myelomonocytic cells has profound implications for their inflammatory phenotype and may trigger the development of vascular disease.
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- 2018
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26. Polemics investigated in a late fifteenth-century Fastnachtspiel (Shrovetide play)
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Claudia Daiber
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Fifteenth ,business.product_category ,biology ,lcsh:History (General) and history of Europe ,Metaphor ,media_common.quotation_subject ,Judaism ,lcsh:D111-203 ,lcsh:Medieval history ,biology.organism_classification ,Moral authority ,Scholarship ,Ruler ,lcsh:D ,Emperor ,Religious studies ,business ,media_common - Abstract
The article analyses the polemics used in the Fastnachtspiel (Shrovetide Play) Der Juden Messias – in scholarship also known as Spil vom Herzog von Burgund − by the meistersinger Hans Folz (1435/40-1513), a barber-surgeon from Nuremberg. The play belongs to a group of Shrovetide plays within Folz’s oeuvre which, under a religious cover, negotiates the given sociological divide in the city of Nuremberg between the Christian and the Jewish communities at the end of the fifteenth century. In its first part, the play systematically stabilizes the Christian side and destabilizes the other, i.e. the Jewish side by directing polemical attacks through the devices of self-accusation and self-flagellation by the Jewish characters. The effect is that the actions of the Christian side are legitimized and any moral hurdles towards condemning the Jewish characters are removed by ultimately equating them with feces and swine. The second part contains a rather ambiguous message since on the one hand the ruler expressis verbis gives his permission to the mob, represented by the jester characters, to rob, rape and oust the Jewish characters. This consenting, on the other hand, prompts a uniting of the mob characters with the ruler. In other words, any moral authority of the ruler – who clearly is a metaphor for the later emperor Maximilian I – is put on a par with the mob and is therefore denied. Whether or not this latter message was appreciated by the city council of Nuremberg at the time remains an open question since there is, to date, no archival proof of the play’s staging nor of its rejection.
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- 2018
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27. Exacerbation of adverse cardiovascular effects of aircraft noise in an animal model of arterial hypertension
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Katie Frenis, Miroslava Kvandova, Andreas Daiber, Konstantina Filippou, Kamil Kus, Rainer Schulz, Sebastian Steven, Kerstin Boengler, Omar Hahad, Sanela Kalinovic, Chiara Trevisan, Katrin Frauenknecht, Mette Sørensen, Klaus-Dieter Schlüter, Johanna Helmstädter, Stefan Chlopicki, Matthias Oelze, Thomas Münzel, Swenja Kröller-Schön, University of Zurich, and Daiber, Andreas
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0301 basic medicine ,Aircraft ,medicine.medical_treatment ,Clinical Biochemistry ,Blood Pressure ,1308 Clinical Biochemistry ,medicine.disease_cause ,Biochemistry ,Mice ,0302 clinical medicine ,Medicine ,Endothelial dysfunction ,lcsh:QH301-705.5 ,lcsh:R5-920 ,NADPH oxidase ,biology ,Cytokine ,Hypertension ,medicine.symptom ,lcsh:Medicine (General) ,Arterial hypertension ,medicine.medical_specialty ,Articles from the Special Issue on Impact of environmental pollution and stress on redox signaling and oxidative stress pathways ,Edited by Thomas Münzel and Andreas Daiber ,10208 Institute of Neuropathology ,610 Medicine & health ,Inflammation ,03 medical and health sciences ,Internal medicine ,Environmental noise exposure ,Animals ,Neuroinflammation ,business.industry ,Organic Chemistry ,Endothelial function ,medicine.disease ,Angiotensin II ,Mice, Inbred C57BL ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,Blood pressure ,lcsh:Biology (General) ,Vascular oxidative stress ,biology.protein ,570 Life sciences ,Endothelium, Vascular ,business ,030217 neurology & neurosurgery ,Oxidative stress ,1605 Organic Chemistry - Abstract
Arterial hypertension is the most important risk factor for the development of cardiovascular disease. Recently, aircraft noise has been shown to be associated with elevated blood pressure, endothelial dysfunction, and oxidative stress. Here, we investigated the potential exacerbated cardiovascular effects of aircraft noise in combination with experimental arterial hypertension. C57BL/6J mice were infused with 0.5 mg/kg/d of angiotensin II for 7 days, exposed to aircraft noise for 7 days at a maximum sound pressure level of 85 dB(A) and a mean sound pressure level of 72 dB(A), or subjected to both stressors. Noise and angiotensin II increased blood pressure, endothelial dysfunction, oxidative stress and inflammation in aortic, cardiac and/or cerebral tissues in single exposure models. In mice subjected to both stressors, most of these risk factors showed potentiated adverse changes. We also found that mice exposed to both noise and ATII had increased phagocytic NADPH oxidase (NOX-2)-mediated superoxide formation, immune cell infiltration (monocytes, neutrophils and T cells) in the aortic wall, astrocyte activation in the brain, enhanced cytokine signaling, and subsequent vascular and cerebral oxidative stress. Exaggerated renal stress response was also observed. In summary, our results show an enhanced adverse cardiovascular effect between environmental noise exposure and arterial hypertension, which is mainly triggered by vascular inflammation and oxidative stress. Mechanistically, noise potentiates neuroinflammation and cerebral oxidative stress, which may be a potential link between both risk factors. The results indicate that a combination of classical (arterial hypertension) and novel (noise exposure) risk factors may be deleterious for cardiovascular health., Graphical abstract Image 1, Highlights • Noise exposure causes non-auditory cardiovascular/cerebral adverse health effects by oxidative stress and inflammation. • Aircraft noise causes exacerbated adverse effects on blood pressure and endothelial dysfunction in hypertensive mice. • Aircraft noise and hypertension potentiate inflammation, ROS formation and oxidative damage in the brain, vessels and heart. • Aircraft noise and hypertension seem to have enhanced adverse effects on stress responses in different organs.
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- 2020
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28. CD40L controls obesity-associated vascular inflammation, oxidative stress, and endothelial dysfunction in high fat diet-treated and db/db mice
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Christoph Knosalla, Fatemeh Kashani, Karl J. Lackner, Philipp S. Wild, Siyer Roohani, Andreas Daiber, Esther Lutgens, Sebastian Steven, Steffen Daub, Christian Becker, Beate Niesler, Yves Gramlich, Michael Hausding, Matthias Oelze, Swenja Kröller-Schön, Mobin Dib, Thomas Münzel, Eberhard Schulz, Alina Hanf, Hartmut Kleinert, and Other departments
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Male ,0301 basic medicine ,Physiology ,Anti-Inflammatory Agents ,Nitric Oxide Synthase Type II ,030204 cardiovascular system & hematology ,Weight Gain ,medicine.disease_cause ,Antioxidants ,chemistry.chemical_compound ,0302 clinical medicine ,Hyperlipidemia ,Endothelial dysfunction ,Mice, Knockout ,biology ,Leptin ,Lipids ,Vasodilation ,Nitric oxide synthase ,Inflammation Mediators ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,CD40 Ligand ,Hyperlipidemias ,Inflammation ,Diet, High-Fat ,03 medical and health sciences ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Humans ,Obesity ,Platelet activation ,TNF Receptor-Associated Factor 6 ,Interleukin-6 ,Cholesterol ,business.industry ,Myocardium ,NADPH Oxidases ,Platelet Activation ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,chemistry ,biology.protein ,Endothelium, Vascular ,business ,Biomarkers ,Oxidative stress - Abstract
Aims CD40 ligand (CD40L) signaling controls vascular oxidative stress and related dysfunction in angiotensin-II-induced arterial hypertension by regulating vascular immune cell recruitment and platelet activation. Here we investigated the role of CD40L in experimental hyperlipidemia. Methods and results Male wild type and CD40L−/− mice (C57BL/6 background) were subjected to high fat diet for sixteen weeks. Weight, cholesterol, HDL, and LDL levels, endothelial function (isometric tension recording), oxidative stress (NADPH oxidase expression, dihydroethidium fluorescence) and inflammatory parameters (inducible nitric oxide synthase, interleukin-6 expression) were assessed. CD40L expression, weight, leptin and lipids were increased, and endothelial dysfunction, oxidative stress and inflammation were more pronounced in wild type mice on a high fat diet, all of which was almost normalized by CD40L deficiency. Similar results were obtained in diabetic db/db mice with CD40/TRAF6 inhibitor (6877002) therapy. In a small human study higher serum sCD40L levels and an inflammatory phenotype were detected in the blood and Aorta ascendens of obese patients (body mass index > 35) that underwent by-pass surgery. Conclusion CD40L controls obesity-associated vascular inflammation, oxidative stress and endothelial dysfunction in mice and potentially humans. Thus, CD40L represents a therapeutic target in lipid metabolic disorders which is a leading cause in cardiovascular disease.
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- 2017
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29. P717Glucagon-like peptide 1 (GLP-1) improves endothelial dysfunction and vascular inflammation in polymicrobial sepsis induced by cecal ligation and puncture (CLP)
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Sebastian Steven, J Helmstaedter, Konstantina Filippou, Sanela Kalinovic, K Frenies, F Pawelke, S. Kroeller-Schoen, Andreas Daiber, Ksenija Vujacic-Mirski, Matthias Oelze, and Thomas Münzel
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Endothelium ,biology ,business.industry ,Inflammation ,Pharmacology ,medicine.disease ,Glucagon-like peptide-1 ,Sepsis ,Cecum ,medicine.anatomical_structure ,medicine ,biology.protein ,medicine.symptom ,Endothelial dysfunction ,Cardiology and Cardiovascular Medicine ,business ,Ligation ,Interleukin 6 - Abstract
Objective Sepsis causes severe hypotension, accompanied by high mortality in the setting of septic shock. LEADER, SUSTAIN-6 and other clinical trials revealed cardioprotective and anti-inflammatory properties of GLP-1 analogs like Liraglutide (Lira). We already demonstrated improved survival by amelioration of disseminated intravasal coagulation (DIC) in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of the GLP-1 degrading enzyme dipeptidylpeptidase-4 (DPP-4). With the present study we aim to investigate the mechanism of protective effects of the GLP-1 analog Lira and the DPP4 inhibitor Linagliptin (Lina) in the clinically relevant sepsis model cecal ligation and puncture (CLP). Methods C57/BL6j and endothelial cell-specific GLP-1 receptor knockout mice (Cdh5crexGLP-1rfl/flmice) were used and sepsis was induced by cecal ligation and puncture (CLP). DPP4 inhibitor (Lina, 5mg/kg/d; 3 days) and GLP-1 analog (Lira, 200μg/kg/d; 3 days) were applied subcutaneously. Aortic vascular function was tested by isometric tension recording. Aorta and heart tissue was used for Western blotting, dot blot and qRT-PCR. Endogenous GLP-1 (7–36 and 9–36) and insulin was determined by ELISA. Blood samples were collected for examination of cell count, oxidative stress and glucose levels. Results Body temperature was increased by CLP and normalized by Lina and Lira. Sham- and Lira- but not Lina-treated septic mice showed low blood glucose levels compared to healthy controls. Acetylcholine-induced (endothelium-dependent) vascular relaxation in aorta was impaired by CLP. This was accompanied by vascular inflammation and elevation of IL-6, iNOS, ICAM-1, and TNF-alpha mRNA levels in aortic tissue. Vascular, cardiac and whole blood oxidative stress were increased by CLP. Furthermore, we detected higher levels of IL-6, 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-NHE) in plasma of CLP animals. Lina and Lira reduced oxidative stress and vascular inflammation, which was accompanied by improved endothelial function. In addition, CLP treatment in endothelial specific knockout mice of the GLP-1r strongly induced mortality compared to WT mice, with the effect being strongest in the Lira-treated group. Conclusion The present study demonstrates that Lina (DPP4 inhibitor) and the GLP-1 analog Lira ameliorate sepsis-induced endothelial dysfunction by reduction of vascular inflammation and oxidative stress. Clinical trials like LEADER and SUSTAIN-6 proved that GLP-1 analogs like Lira have cardioprotective effects in T2DM patients. The present study, performed in a clinically relevant model of polymicrobial sepsis, reveals that the known cardioprotective effects of GLP-1 might be translated to other diseases which affect the cardiovascular system like sepsis, underlining the potent anti-inflammatory effects of GLP-1 analogs.
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- 2019
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30. The anti-cancer drug doxorubicin induces substantial epigenetic changes in cultured cardiomyocytes
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Thomas Münzel, Huige Li, Andreas Daiber, Alina Hanf, Adrian Manea, and Matthias Oelze
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0301 basic medicine ,Programmed cell death ,Methyltransferase ,Apoptosis ,Toxicology ,medicine.disease_cause ,Histone Deacetylases ,Epigenesis, Genetic ,Histones ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Myocytes, Cardiac ,Epigenetics ,Cells, Cultured ,Histone Demethylases ,Antibiotics, Antineoplastic ,biology ,Dose-Response Relationship, Drug ,Histone deacetylase 2 ,Chemistry ,General Medicine ,Epigenome ,Hydrogen Peroxide ,Cardiotoxicity ,Cell biology ,Rats ,Oxidative Stress ,030104 developmental biology ,Histone ,Acetylation ,Doxorubicin ,030220 oncology & carcinogenesis ,biology.protein ,Oxidative stress ,Biomarkers - Abstract
The anthracycline doxorubicin (DOX) is widely used in cancer therapy with the limitation of cardiotoxicity leading to the development of congestive heart failure. DOX-induced oxidative stress and changes of the phosphoproteome as well as epigenome were described but the exact mechanisms of the adverse long-term effects are still elusive. Here, we tested the impact of DOX treatment on cell death, oxidative stress parameters and expression profiles of proteins involved in epigenetic pathways in a cardiomyocyte cell culture model. Markers of oxidative stress, apoptosis and expression of proteins involved in epigenetic processes were assessed by immunoblotting in cultured rat myoblasts (H9c2) upon treatment with DOX (1 or 5 μM for 24 or 48 h) in adherent viable and detached apoptotic cells. The apoptosis markers cleaved caspase-3 and fractin as well as oxidative stress markers 3-nitrotyrosine and malondialdehyde were dose-dependently increased by DOX treatment. Histone deacetylases (SIRT1 and HDAC2), histone lysine demethylases (KDM3A and LSD1) and histone lysine methyltransferases (SET7 and SMYD1) were significantly regulated by DOX treatment with generation of cleaved protein fragments and posttranslational modifications. Overall, we found significant decrease in histone 3 acetylation in DOX-treated cells. DOX treatment of cultured cardiomyocyte precursor cells causes severe cell death by apoptosis associated with cellular oxidative stress. In addition, significant regulation of proteins involved in epigenetic processes and changes in global histone 3 acetylation were observed. However, the significance and clinical impact of these changes remain elusive.
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- 2019
31. Apolipoprotein E Deficiency Causes Endothelial Dysfunction in the Mouse Retina
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Can Yuksel, Andreas Daiber, Aytan Musayeva, Panagiotis Laspas, Christoph Brochhausen, Ning Xia, Norbert Pfeiffer, Mayagozel B. Zhutdieva, Matthias Oelze, Jenia Kouchek Zadeh, Huige Li, and Adrian Gericke
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Aging ,medicine.medical_specialty ,Article Subject ,Endothelium ,Mice, Knockout, ApoE ,Hypercholesterolemia ,medicine.disease_cause ,Biochemistry ,Retina ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Apolipoproteins E ,Retinal Diseases ,Internal medicine ,medicine ,Animals ,Endothelial dysfunction ,lcsh:QH573-671 ,NADPH oxidase ,biology ,lcsh:Cytology ,Retinal Vessels ,Retinal ,Cell Biology ,General Medicine ,medicine.disease ,Arterioles ,Oxidative Stress ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Retinal ganglion cell ,030221 ophthalmology & optometry ,Optic nerve ,biology.protein ,Endothelium, Vascular ,030217 neurology & neurosurgery ,Oxidative stress ,Research Article - Abstract
Objective. Atherogenic lipoproteins may impair vascular reactivity consecutively causing tissue damage in multiple organs via abnormal perfusion and excessive reactive oxygen species generation. We tested the hypothesis that chronic hypercholesterolemia causes endothelial dysfunction and cell loss in the retina. Methods. Twelve-month-old apolipoprotein E-deficient (ApoE-/-) mice and age-matched wild-type controls were used in this study (n=8 per genotype for each experiment). Intraocular pressure, blood pressure, and ocular perfusion pressure were determined. Retinal arteriole responses were studied in vitro, and reactive oxygen and nitrogen species were quantified in the retinal and optic nerve cryosections. The expression of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and the NADPH oxidase isoforms, NOX1, NOX2, and NOX4, were determined in retinal cryosections by immunofluorescence microscopy. Pro- and antioxidant redox genes were quantified in retinal explants by PCR. Moreover, cell number in the retinal ganglion cell layer and axon number in the optic nerve was calculated. Results. Responses to the endothelium-dependent vasodilator, acetylcholine, were markedly impaired in retinal arterioles of ApoE-/- mice (P<0.01). LOX-1 (P=0.0007) and NOX2 (P=0.0027) expressions as well as levels of reactive oxygen species (P=0.0022) were increased in blood vessels but not in other retinal structures. In contrast, reactive nitrogen species were barely detectable in both mouse genotypes. Messenger RNA for HIF-1α, VEGF-A, NOX1, and NOX2, but also for various antioxidant redox genes was elevated in the retina of ApoE-/- mice. Total cell number in the retinal ganglion cell layer did not differ between ApoE-/- and wild-type mice (P=0.2171). Also, axon number in the optic nerve did not differ between ApoE-/- and wild-type mice (P=0.6435). Conclusion. Apolipoprotein E deficiency induces oxidative stress and endothelial dysfunction in retinal arterioles, which may trigger hypoxia in the retinal tissue. Oxidative stress in nonvascular retinal tissue appears to be prevented by the upregulation of antioxidant redox enzymes, resulting in neuron preservation.
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- 2019
32. Endothelial α1AMPK modulates angiotensin II-mediated vascular inflammation and dysfunction
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Andreas Daiber, Marc Foretz, Matthias Oelze, Sabine Kossmann, Philip Wenzel, Thomas Münzel, Jeremy Lagrange, Katie Frenis, John F. Keaney, Eberhard Schulz, Thi Lan P. Tran, Thomas Jansen, Benoit Viollet, Swenja Kröller-Schön, Miroslawa Kvandová, Sanela Kalinovic, Johannes Gutenberg - Universität Mainz (JGU), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), and Johannes Gutenberg - University of Mainz (JGU)
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Male ,0301 basic medicine ,MESH: Inflammation ,Physiology ,AMP-Activated Protein Kinases ,030204 cardiovascular system & hematology ,medicine.disease_cause ,MESH: Mice, Knockout ,Antioxidants ,Mice ,0302 clinical medicine ,MESH: Animals ,Endothelial dysfunction ,MESH: AMP-Activated Protein Kinases ,Vascular inflammation ,Mice, Knockout ,NADPH oxidase ,MESH: Oxidative Stress ,biology ,MESH: Heme Oxygenase-1 ,Chemistry ,Angiotensin II ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,α1AMPK ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,Integrin alpha M ,Knockout mouse ,MESH: Angiotensin II ,MESH: Membrane Proteins ,MESH: Endothelium, Vascular ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,03 medical and health sciences ,Downregulation and upregulation ,MESH: Mice, Inbred C57BL ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,MESH: Mice ,Inflammation ,Macrophages ,MESH: Antioxidants ,Membrane Proteins ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,medicine.disease ,MESH: Male ,Mice, Inbred C57BL ,Heme oxygenase ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,biology.protein ,Endothelium, Vascular ,Reactive oxygen species ,Heme Oxygenase-1 ,Oxidative stress - Abstract
International audience; Mice with a global deletion of α1AMPK are characterized by endothelial dysfunction and NADPH oxidase subunit 2 (NOX-2)-mediated vascular oxidative stress. However, the underlying mechanisms are incompletely understood and may involve endothelial NOX-2 upregulation or facilitated vascular infiltration of phagocytic cells. Therefore, the current study was designed to investigate the vascular effects of chronic angiotensin II (AngII) infusion in mice with an endothelial-specific α1AMPK deletion. A mouse strain with endothelial-specific α1AMPK deletion was generated by breeding α1AMPKflox/flox mice with TekCre+ or Cadh5Cre+ mice. Chronic AngII infusion (0.5 mg/kg/day for 7day) caused mild endothelial dysfunction in wild-type mice that was significantly aggravated in endothelial α1AMPK knockout mice. Aortic NOX-2 and CD68 expression were increased, indicating that infiltrating leukocytes may significantly contribute to enhanced vascular oxidative stress. Flow cytometry revealed a higher abundance of aortic CD90.2+ T-cells, CD11b+F4/80+ macrophages and Ly6G-Ly6C+ monocytes. Vascular mRNA expression of monocyte chemoattractant protein 1, CCL5 and vascular cell adhesion molecule 1 was enhanced in AngII-infused mice lacking endothelial α1AMPK, facilitating the recruitment of inflammatory cells to the vessel wall. In addition, AngII-induced upregulation of cytoprotective heme oxygenase 1 (HO-1) was blunted in mice with endothelial α1AMPK deletion, compatible with an impaired antioxidant defense in these animals. In summary, endothelial expressed α1AMPK limits the recruitment of inflammatory cells to the vessel wall and maintains HO-1 mediated antioxidant defense. Both mechanisms reduce vascular oxidative damage and preserve endothelial function during chronic AngII treatment.
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- 2019
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33. Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease
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Marin Kuntic, Katie Frenis, Ksenija Vujacic-Mirski, Matthias Oelze, Swenja Kröller-Schön, Sanela Kalinovic, Thomas Münzel, Maria Teresa Bayo Jimenez, Johanna Helmstädter, Sebastian Steven, and Andreas Daiber
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0301 basic medicine ,Aging ,Antioxidant ,medicine.medical_treatment ,Inflammation ,Disease ,Review Article ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Biochemistry ,Superoxide dismutase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Medicine ,Humans ,lcsh:QH573-671 ,Cause of death ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,business.industry ,lcsh:Cytology ,Cell Biology ,General Medicine ,Glutathione ,Oxidative Stress ,030104 developmental biology ,chemistry ,Cardiovascular Diseases ,Immunology ,biology.protein ,medicine.symptom ,business ,Oxidative stress - Abstract
Cardiovascular disease is a leading cause of death and reduced quality of life, proven by the latest data of the Global Burden of Disease Study, and is only gaining in prevalence worldwide. Clinical trials have identified chronic inflammatory disorders as cardiovascular risks, and recent research has revealed a contribution by various inflammatory cells to vascular oxidative stress. Atherosclerosis and cardiovascular disease are closely associated with inflammation, probably due to the close interaction of inflammation with oxidative stress. Classical therapies for inflammatory disorders have demonstrated protective effects in various models of cardiovascular disease; especially established drugs with pleiotropic immunomodulatory properties have proven beneficial cardiovascular effects; normalization of oxidative stress seems to be a common feature of these therapies. The close link between inflammation and redox balance was also supported by reports on aggravated inflammatory phenotype in the absence of antioxidant defense proteins (e.g., superoxide dismutases, heme oxygenase-1, and glutathione peroxidases) or overexpression of reactive oxygen species producing enzymes (e.g., NADPH oxidases). The value of immunomodulation for the treatment of cardiovascular disease was recently supported by large-scale clinical trials demonstrating reduced cardiovascular mortality in patients with established atherosclerotic disease when treated by highly specific anti-inflammatory therapies (e.g., using monoclonal antibodies against cytokines). Modern antidiabetic cardiovascular drugs (e.g., SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 analogs) seem to share these immunomodulatory properties and display potent antioxidant effects, all of which may explain their successful lowering of cardiovascular risk.
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- 2019
34. New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease
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Matthias Oelze, Thomas Münzel, Swenja Kröller-Schön, Sebastian Steven, Ning Xia, Alina Hanf, Huige Li, and Andreas Daiber
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0301 basic medicine ,Adipose tissue ,Review ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease_cause ,endothelial dysfunction ,Epigenesis, Genetic ,lcsh:Chemistry ,0302 clinical medicine ,Enos ,cardiovascular disease ,eNOS uncoupling ,oxidative stress ,Endothelial dysfunction ,lcsh:QH301-705.5 ,Spectroscopy ,environmental stressors ,biology ,General Medicine ,Computer Science Applications ,medicine.anatomical_structure ,Cardiovascular Diseases ,medicine.symptom ,Oxidation-Reduction ,Cell signaling ,Endothelium ,Nitric Oxide Synthase Type III ,Inflammation ,Models, Biological ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,life style/behavioral health risk factors ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,business.industry ,Organic Chemistry ,medicine.disease ,biology.organism_classification ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Socioeconomic Factors ,inflammation ,Soluble guanylyl cyclase ,business ,Oxidative stress - Abstract
The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even “uncoupling” of the enzyme by adverse regulation of well-defined “redox switches” in eNOS itself or up-/down-stream signaling molecules. Of note, not only eNOS function and activity in the endothelium are essential for vascular integrity and homeostasis, but also eNOS in perivascular adipose tissue plays an important role for these processes. Accordingly, eNOS protein represents an attractive therapeutic target that, so far, was not pharmacologically exploited. With our present work, we want to provide an overview on recent advances and future therapeutic strategies that could be used to target eNOS activity and function in cardiovascular (and other) diseases, including life style changes and epigenetic modulations. We highlight the redox-regulatory mechanisms in eNOS function and up- and down-stream signaling pathways (e.g., tetrahydrobiopterin metabolism and soluble guanylyl cyclase/cGMP pathway) and their potential pharmacological exploitation.
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- 2019
35. Antioxidant effects of resveratrol in the cardiovascular system
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Andreas Daiber, Huige Li, Ning Xia, and Ulrich Förstermann
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0301 basic medicine ,Pharmacology ,Oxidase test ,Antioxidant ,endocrine system diseases ,biology ,Superoxide ,Sirtuin 1 ,organic chemicals ,medicine.medical_treatment ,food and beverages ,Mitochondrion ,Resveratrol ,medicine.disease_cause ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,Biochemistry ,medicine ,biology.protein ,Protein deacetylase ,Oxidative stress - Abstract
The antioxidant effects of resveratrol (3,5,4'-trihydroxy-trans-stilbene) contribute substantially to the health benefits of this compound. Resveratrol has been shown to be a scavenger of a number of free radicals. However, the direct scavenging activities of resveratrol are relatively poor. The antioxidant properties of resveratrol in vivo are more likely to be attributable to its effect as a gene regulator. Resveratrol inhibits NADPH oxidase-mediated production of ROS by down-regulating the expression and activity of the oxidase. This polyphenolic compound reduces mitochondrial superoxide generation by stimulating mitochondria biogenesis. Resveratrol prevents superoxide production from uncoupled endothelial nitric oxide synthase by up-regulating the tetrahydrobiopterin-synthesizing enzyme GTP cyclohydrolase I. In addition, resveratrol increases the expression of various antioxidant enzymes. Some of the gene-regulating effects of resveratrol are mediated by the histone/protein deacetylase sirtuin 1 or by the nuclear factor-E2-related factor-2. In this review article, we have also summarized the cardiovascular effects of resveratrol observed in clinical trials. Linked articles This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
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- 2016
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36. Influence of Sae-regulated and Agr-regulated factors on the escape ofStaphylococcus aureusfrom human macrophages
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Lisa Münzenmayer, Ellen Daiber, Berit Schulte, Tobias Geiger, Martin Fraunholz, Christiane Wolz, and Stella E. Autenrieth
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0301 basic medicine ,Cell type ,Intracellular parasite ,030106 microbiology ,Immunology ,Mutant ,Inflammasome ,Biology ,medicine.disease ,Microbiology ,03 medical and health sciences ,Cytoplasm ,Virology ,medicine ,Cell damage ,Intracellular ,Phagosome ,medicine.drug - Abstract
Although Staphylococcus aureus is not a classical intracellular pathogen, it can survive within phagocytes and many other cell types. However, the pathogen is also able to escape from cells by mechanisms that are only partially understood. We analysed a series of isogenic S. aureus mutants of the USA300 derivative JE2 for their capacity to destroy human macrophages from within. Intracellular S. aureus JE2 caused severe cell damage in human macrophages and could efficiently escape from within the cells. To obtain this full escape phenotype including an intermittent residency in the cytoplasm, the combined action of the regulatory systems Sae and Agr is required. Mutants in Sae or mutants deficient in the Sae target genes lukAB and pvl remained in high numbers within the macrophages causing reduced cell damage. Mutants in the regulatory system Agr or in the Agr target gene psmα were largely similar to wild-type bacteria concerning cell damage and escape efficiency. However, these strains were rarely detectable in the cytoplasm, emphasizing the role of phenol-soluble modulins (PSMs) for phagosomal escape. Thus, Sae-regulated toxins largely determine damage and escape from within macrophages, whereas PSMs are mainly responsible for the escape from the phagosome into the cytoplasm. Damage of macrophages induced by intracellular bacteria was linked neither to activation of apoptosis-related caspase 3, 7 or 8 nor to NLRP3-dependent inflammasome activation.
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- 2016
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37. Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function
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Thomas Münzel, Andreas Daiber, Fabio Di Lisa, Eberhard Schulz, Swenja Kröller-Schön, Matthias Oelze, and Sebastian Steven
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0301 basic medicine ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,NADPH oxidase ,Antioxidant ,biology ,Superoxide ,medicine.medical_treatment ,Mitochondrion ,medicine.disease_cause ,03 medical and health sciences ,chemistry.chemical_compound ,Crosstalk (biology) ,030104 developmental biology ,chemistry ,Biochemistry ,biology.protein ,medicine ,Reactive nitrogen species ,Oxidative stress - Abstract
Cardiovascular diseases are associated with and/or caused by oxidative stress. This concept has been proven by using the approach of genetic deletion of reactive species producing (pro-oxidant) enzymes as well as by the overexpression of reactive species detoxifying (antioxidant) enzymes leading to a marked reduction of reactive oxygen and nitrogen species (RONS) and in parallel to an amelioration of the severity of diseases. Likewise, the development and progression of cardiovascular diseases is aggravated by overexpression of RONS producing enzymes as well as deletion of antioxidant RONS detoxifying enzymes. Thus, the consequences of the interaction (redox crosstalk) of superoxide/hydrogen peroxide produced by mitochondria with other ROS producing enzymes such as NADPH oxidases (Nox) are of outstanding importance and will be discussed including the consequences for endothelial nitric oxide synthase (eNOS) uncoupling as well as the redox regulation of the vascular function/tone in general (soluble guanylyl cyclase, endothelin-1, prostanoid synthesis). Pathways and potential mechanisms leading to this crosstalk will be analysed in detail and highlighted by selected examples from the current literature including hypoxia, angiotensin II-induced hypertension, nitrate tolerance, aging and others. The general concept of redox-based activation of RONS sources via "kindling radicals" and enzyme-specific "redox switches" will be discussed providing evidence that mitochondria represent key players and amplifiers of the burden of oxidative stress. Linked articles This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
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- 2016
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38. Uncoupling of Endothelial Nitric Oxide Synthase in Perivascular Adipose Tissue of Diet-Induced Obese Mice
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Alice Habermeier, Andreas Daiber, Ellen I. Closs, Yuliya Mikhed, Adrian Gericke, Ning Xia, Huige Li, Ulrich Förstermann, Gisela Reifenberg, Thomas Münzel, and Sven Horke
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Male ,0301 basic medicine ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Vasodilator Agents ,Adipose tissue ,Aorta, Thoracic ,Vasodilation ,030204 cardiovascular system & hematology ,Arginine ,Diet, High-Fat ,Nitric Oxide ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Adipokines ,Superoxides ,Enos ,Internal medicine ,Paracrine Communication ,Adipocytes ,medicine ,Animals ,Obesity ,Enzyme Inhibitors ,Phosphorylation ,Adiposity ,Arginase ,Dose-Response Relationship, Drug ,biology ,biology.organism_classification ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Adipose Tissue ,chemistry ,Cytokines ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine ,Diet-induced obese ,Signal Transduction ,Myograph - Abstract
Objective— The present study was conducted to investigate the contribution of perivascular adipose tissue (PVAT) to vascular dysfunction in a mouse model of diet-induced obesity. Approach and Results— Obesity was induced in male C57BL/6J mice with a high-fat diet for 20 weeks, and vascular function was studied with myograph. In PVAT-free aortas isolated from obese mice, the endothelium-dependent, nitric oxide–mediated vasodilator response to acetylcholine remained normal. In contrast, a clear reduction in the vasodilator response to acetylcholine was observed in aortas from obese mice when PVAT was left in place. Adipocytes in PVAT were clearly positive in endothelial nitric oxide synthase (eNOS) staining, and PVAT nitric oxide production was significantly reduced in obese mice. High-fat diet had no effect on eNOS expression but led to eNOS uncoupling, evidenced by diminished superoxide production in PVAT after eNOS inhibition. As mechanisms for eNOS uncoupling, arginase induction and l -arginine deficiency were observed in PVAT. Obesity-induced vascular dysfunction could be reversed by ex vivo l -arginine treatment and arginase inhibition. Conclusions— Diet-induced obesity leads to l -arginine deficiency and eNOS uncoupling in PVAT. The combination therapy with l -arginine and arginase inhibitors may represent a novel therapeutic strategy for obesity-induced vascular disease.
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- 2016
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39. The AMP-Activated Protein Kinase Plays a Role in Antioxidant Defense and Regulation of Vascular Inflammation
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Swenja Kröller-Schön, Thomas Jansen, Miroslava Kvandova, Thomas Münzel, Eberhard Schulz, Paul Stamm, Andreas Daiber, and Katie Frenis
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0301 basic medicine ,hypertension ,Endothelium ,Physiology ,Clinical Biochemistry ,Inflammation ,Context (language use) ,Review ,Pharmacology ,medicine.disease_cause ,Biochemistry ,endothelial dysfunction ,03 medical and health sciences ,0302 clinical medicine ,AMP-activated protein kinase ,vascular inflammation ,oxidative stress ,Medicine ,Endothelial dysfunction ,Protein kinase A ,Molecular Biology ,biology ,business.industry ,lcsh:RM1-950 ,AMPK ,Cell Biology ,medicine.disease ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,medicine.symptom ,business ,Oxidative stress - Abstract
Cardiovascular diseases represent the leading cause of global deaths and life years spent with a severe disability. Endothelial dysfunction and vascular oxidative stress are early precursors of atherosclerotic processes in the vascular wall, all of which are hallmarks in the development of cardiovascular diseases and predictors of future cardiovascular events. There is growing evidence that inflammatory processes represent a major trigger for endothelial dysfunction, vascular oxidative stress and atherosclerosis and clinical data identified inflammation as a cardiovascular risk factor on its own. AMP-activated protein kinase (AMPK) is a central enzyme of cellular energy balance and metabolism that has been shown to confer cardio-protection and antioxidant defense which thereby contributes to vascular health. Interestingly, AMPK is also redox-regulated itself. We have previously shown that AMPK largely contributes to a healthy endothelium, confers potent antioxidant effects and prevents arterial hypertension. Recently, we provided deep mechanistic insights into the role of AMPK in cardiovascular protection and redox homeostasis by studies on arterial hypertension in endothelial and myelomonocytic cell-specific AMPK knockout (Cadh5CrexAMPKfl/fl and LysMCrexAMPKfl/fl) mice. Using these cell-specific knockout mice, we revealed the potent anti-inflammatory properties of AMPK representing the molecular basis of the antihypertensive effects of AMPK. Here, we discuss our own findings in the context of literature data with respect to the anti-inflammatory and antioxidant effects of AMPK in the specific setting of arterial hypertension as well as cardiovascular diseases in general.
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- 2020
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40. Development and validation of an analytical assay for electrochemical detection and quantification of protein‐bound 3‐nitrotyrosine in biological samples and comparison with classical, antibody‐based methods
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Thomas Münzel, Sebastian Steven, Sanela Kalinovic, Ksenija Vujacic Mirski, Swenja Kröller-Schön, Andreas Daiber, and Matthias Oelze
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3-nitrotyrosine ,Chromatography ,biology ,Chemistry ,Genetics ,biology.protein ,Electrochemical detection ,Antibody ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2020
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41. Short‐term e‐cigarette vapor exposure causes vascular oxidative stress and dysfunction ‐ evidence for a close connection to brain damage and a key role of the phagocytic NADPH oxidase (NOX‐2)
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Frank P. Schmidt, Sebastian Steven, Swenja Kröller-Schön, Katie Frenis, Andreas Daiber, Franco Varveri, Thorsten Hoffmann, Konstantina Filippou, Marin Kuntic, Vivienne Brückl, Omar Hahad, Regina Huesmann, Ahmad Al Zuabi, Matthias Oelze, Tommaso Gori, Thomas Münzel, Paul Stamm, Sanela Kalinovic, Maria Teresa Bayo Jimenez, Steffen Daub, John F. Keaney, Miroslava Kvandova, and Ksenija Vujacic-Mirski
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NADPH oxidase ,biology ,Chemistry ,Brain damage ,medicine.disease_cause ,Biochemistry ,Cell biology ,Connection (mathematics) ,Genetics ,medicine ,biology.protein ,medicine.symptom ,Molecular Biology ,Oxidative stress ,NOx ,Biotechnology - Published
- 2020
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42. The exposome concept for assessment of environmental health risks – role of redox biology and oxidative stress.
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Daiber, Andreas and Münzel, Thomas
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- *
HEALTH risk assessment , *ENVIRONMENTAL risk assessment , *ENVIRONMENTAL exposure , *OXIDATION-reduction reaction , *BIOLOGY , *OXIDATIVE stress - Published
- 2024
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43. Crucial role for Nox2 and sleep deprivation in aircraft noise-induced vascular and cerebral oxidative stress, inflammation, and gene regulation
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Erwin R. Schmidt, Swenja Kröller-Schön, Philipp S. Wild, Axel Heimann, Katrin Frauenknecht, Katie Frenis, Sanela Kalinovic, Ksenija Vujacic-Mirski, Konstantina Filippou, Sebastian Steven, Matthias Klein, Markus Dudek, Markus Bosmann, Miroslava Kvandova, Hanke Mollnau, Omar Hahad, Axel Methner, Antonio Pinto, Tobias Bopp, Matthias Oelze, Thomas Münzel, Steffen Rapp, Frank P. Schmidt, Andreas Daiber, University of Zurich, and Münzel, Thomas
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0301 basic medicine ,medicine.medical_specialty ,Endothelium ,Aircraft ,10208 Institute of Neuropathology ,Inflammation ,610 Medicine & health ,030204 cardiovascular system & hematology ,Systemic inflammation ,medicine.disease_cause ,2705 Cardiology and Cardiovascular Medicine ,03 medical and health sciences ,0302 clinical medicine ,Basic Science ,Vascular Biology ,Internal medicine ,eNOS uncoupling ,medicine ,Humans ,Endothelial dysfunction ,business.industry ,Environmental stressor ,Cerebral redox balance ,medicine.disease ,Sleep deprivation ,Noise ,Oxidative Stress ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,NADPH oxidase-derived oxidative stress ,570 Life sciences ,biology ,medicine.symptom ,business ,Cardiology and Cardiovascular Medicine ,Oxidative stress ,Noise exposure - Abstract
Aims Aircraft noise causes endothelial dysfunction, oxidative stress, and inflammation. Transportation noise increases the incidence of coronary artery disease, hypertension, and stroke. The underlying mechanisms are not well understood. Herein, we investigated effects of phagocyte-type NADPH oxidase (Nox2) knockout and different noise protocols (around-the-clock, sleep/awake phase noise) on vascular and cerebral complications in mice. Methods and results C57BL/6j and Nox2 −/− (gp91phox −/−) mice were exposed to aircraft noise (maximum sound level of 85 dB(A), average sound pressure level of 72 dB(A)) around-the-clock or during sleep/awake phases for 1, 2, and 4 days. Adverse effects of around-the-clock noise on the vasculature and brain were mostly prevented by Nox2 deficiency. Around-the-clock aircraft noise of the mice caused the most pronounced vascular effects and dysregulation of Foxo3/circadian clock as revealed by next generation sequencing (NGS), suggesting impaired sleep quality in exposed mice. Accordingly, sleep but not awake phase noise caused increased blood pressure, endothelial dysfunction, increased markers of vascular/systemic oxidative stress, and inflammation. Noise also caused cerebral oxidative stress and inflammation, endothelial and neuronal nitric oxide synthase (e/nNOS) uncoupling, nNOS mRNA and protein down-regulation, and Nox2 activation. NGS revealed similarities in adverse gene regulation between around-the-clock and sleep phase noise. In patients with established coronary artery disease, night-time aircraft noise increased oxidative stress, and inflammation biomarkers in serum. Conclusion Aircraft noise increases vascular and cerebral oxidative stress via Nox2. Sleep deprivation and/or fragmentation caused by noise triggers vascular dysfunction. Thus, preventive measures that reduce night-time aircraft noise are warranted.
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- 2018
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44. Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D: a novel mechanism for an old drug
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Peter Brouckaert, Kyriakos E. Kypreos, Voahanginirina Randriamboavonjy, Andreas Papapetropoulos, Andreas Daiber, Sebastian Steven, Derek J. Hausenloy, Ingrid Fleming, Efstathios K. Iliodromitis, Ioanna Andreadou, Athanasia Chatzianastasiou, and Sofia-Iris Bibli
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0301 basic medicine ,Adult ,Male ,genetic structures ,Nitric Oxide Synthase Type III ,Physiology ,Mice, Knockout, ApoE ,Nitrosation ,Ischemia ,Myocardial Infarction ,Myocardial Reperfusion Injury ,030204 cardiovascular system & hematology ,Pharmacology ,03 medical and health sciences ,Cyclophilins ,Necrosis ,Nitroglycerin ,0302 clinical medicine ,Reperfusion therapy ,Enos ,Physiology (medical) ,medicine ,Animals ,Humans ,Myocytes, Cardiac ,Nitric Oxide Donors ,Endothelial dysfunction ,Enzyme Inhibitors ,Aged ,Peptidylprolyl isomerase ,Cardioprotection ,biology ,business.industry ,Original Articles ,Middle Aged ,medicine.disease ,biology.organism_classification ,eye diseases ,Nitric oxide synthase ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Knockout mouse ,biology.protein ,Female ,Cardiology and Cardiovascular Medicine ,business ,Signal Transduction - Abstract
Aims Nitroglycerine (NTG) given prior to an ischaemic insult exerts cardioprotective effects. However, whether administration of an acute low dose of NTG in a clinically relevant manner following an ischaemic episode limits infarct size, has not yet been explored. Methods and results Adult mice were subjected to acute myocardial infarction in vivo and then treated with vehicle or low-dose NTG prior to reperfusion. This treatment regimen minimized myocardial infarct size without affecting haemodynamic parameters but the protective effect was absent in mice rendered tolerant to the drug. Mechanistically, NTG was shown to nitrosate and inhibit cyclophilin D (CypD), and NTG administration failed to limit infarct size in CypD knockout mice. Additional experiments revealed lack of the NTG protective effect following genetic (knockout mice) or pharmacological inhibition (L-NAME treatment) of the endothelial nitric oxide synthase (eNOS). The protective effect of NTG was attributed to preservation of the eNOS dimer. Moreover, NTG retained its cardioprotective effects in a model of endothelial dysfunction (ApoE knockout) by preserving CypD nitrosation. Human ischaemic heart biopsies revealed reduced eNOS activity and exhibited reduced CypD nitrosation. Conclusion Low-dose NTG given prior to reperfusion reduces myocardial infarct size by preserving eNOS function, and the subsequent eNOS-dependent S-nitrosation of CypD, inhibiting cardiomyocyte necrosis. This novel pharmacological action of NTG warrants confirmation in clinical studies, although our data in human biopsies provide promising preliminary results.
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- 2018
45. The potential of aldehyde dehydrogenase 2 as a therapeutic target in cardiovascular disease
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Andreas Daiber and Thomas Münzel
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0301 basic medicine ,Clinical Biochemistry ,Aldehyde dehydrogenase ,medicine.disease_cause ,Antioxidants ,03 medical and health sciences ,chemistry.chemical_compound ,Detoxification ,Drug Discovery ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Pharmacology ,Ethanol ,biology ,Aldehyde Dehydrogenase, Mitochondrial ,Mitochondrial Aldehyde Dehydrogenase ,Acetaldehyde ,Cardiovascular Agents ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,Biochemistry ,chemistry ,Cardiovascular Diseases ,Drug Design ,Cardiovascular agent ,Disulfiram ,biology.protein ,Molecular Medicine ,Oxidative stress ,medicine.drug - Abstract
Mitochondrial aldehyde dehydrogenase (ALDH-2) plays a major role in the ethanol detoxification pathway by removing acetaldehyde. Therefore, ALDH-2 inhibitors such as disulfiram represent the first therapeutic targeting of ALDH-2 for alcoholism therapy. Areas covered: Recently, ALDH-2 was identified as an essential bioactivating enzyme of the anti-ischemic organic nitrate nitroglycerin, bringing ALDH-2 again into the focus of clinical interest. Mechanistic studies on the nitroglycerin bioactivation process revealed that during bioconversion of nitroglycerin and in the presence of reactive oxygen and nitrogen species the active site thiols of ALDH-2 are oxidized and the enzyme activity is lost. Thus, ALDH-2 activity represents a useful marker for cardiovascular oxidative stress, a concept, which has been meanwhile supported by a number of animal disease models. Mechanistic studies on the protective role of ALDH-2 in different disease processes identified the detoxification of 4-hydroxynonenal by ALDH-2 as a fundamental process of cardiovascular, cerebral and antioxidant protection. Expert opinion: The most recent therapeutic exploitation of ALDH-2 includes activators of the enzyme such as Alda-1 but also cell-based therapies (ALDH-bright cells) that deserve further clinical characterization in the future.
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- 2018
46. Environmental Noise and the Cardiovascular System
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Johannes Herzog, Mette Sørensen, Sebastian Steven, Thomas Münzel, Andreas Daiber, and Frank P. Schmidt
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Sleep Wake Disorders ,medicine.medical_specialty ,Blood Pressure ,030204 cardiovascular system & hematology ,010501 environmental sciences ,medicine.disease_cause ,01 natural sciences ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Animals ,Humans ,Myocardial infarction ,Endothelial dysfunction ,Stroke ,0105 earth and related environmental sciences ,NADPH oxidase ,biology ,business.industry ,Environmental Exposure ,medicine.disease ,Oxidative Stress ,Cardiovascular Diseases ,Heart failure ,biology.protein ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,Noise ,Oxidative stress ,Hormone - Abstract
Noise has been found associated with annoyance, stress, sleep disturbance, and impaired cognitive performance. Furthermore, epidemiological studies have found that environmental noise is associated with an increased incidence of arterial hypertension, myocardial infarction, heart failure, and stroke. Observational and translational studies indicate that especially nighttime noise increases levels of stress hormones and vascular oxidative stress, which may lead to endothelial dysfunction and arterial hypertension. Novel experimental studies found aircraft noise to be associated with oxidative stress–induced vascular damage, mediated by activation of the NADPH oxidase, uncoupling of endothelial nitric oxide synthase, and vascular infiltration with inflammatory cells. Transcriptome analysis of aortic tissues from animals exposed to aircraft noise revealed changes in the expression of genes responsible for the regulation of vascular function, vascular remodeling, and cell death. This review focuses on the mechanisms and the epidemiology of noise-induced cardiovascular diseases and provides novel insight into the mechanisms underlying noise-induced vascular damage.
- Published
- 2018
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47. Comparison of pulmonary and systemic NO- and $PGI_{2}$-dependent endothelial function in diabetic mice
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Agnieszka Jasztal, Barbara Sitek, Łukasz Mateuszuk, Elzbieta Buczek, Mobin Dib, Stefan Chlopicki, Antonina Chmura-Skirlinska, Andreas Daiber, Sebastian Steven, Andrzej Fedorowicz, and Elżbieta Czarnowska
- Subjects
0301 basic medicine ,Aging ,medicine.medical_specialty ,Article Subject ,Endothelium ,Vasodilation ,030204 cardiovascular system & hematology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Enos ,Internal medicine ,Diabetes mellitus ,medicine.artery ,Medicine ,Endothelial dysfunction ,lcsh:QH573-671 ,Aorta ,Lung ,biology ,business.industry ,lcsh:Cytology ,Cell Biology ,General Medicine ,biology.organism_classification ,medicine.disease ,Pulmonary hypertension ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,business - Abstract
Diabetes increases the risk of pulmonary hypertension and is associated with alterations in pulmonary vascular function. Still, it is not clear whether alterations in the phenotype of pulmonary endothelium induced by diabetes are distinct, as compared to peripheral endothelium. In the present work, we characterized differences between diabetic complications in the lung and aorta in db/db mice with advanced diabetes. Male, 20-week-old db/db mice displayed increased HbA1c and glucose concentration compatible with advanced diabetes. Diabetic lungs had signs of mild fibrosis, and pulmonary endothelium displayed significantly ultrastructural changes. In the isolated, perfused lung from db/db mice, filtration coefficient (Kf,c) and contractile response to TXA2 analogue were enhanced, while endothelial NO-dependent modulation of pulmonary response to hypoxic ventilation and cumulative production of NO2− were impaired, with no changes in immunostaining for eNOS expression. In turn, 6-keto-PGF1α release from the isolated lung from db/db mice was increased, as well as immunostaining of thrombomodulin (CD141). In contrast to the lung, NO-dependent, acetylcholine-induced vasodilation, ionophore-stimulated NO2− generation, and production of 6-keto-PGF1α were all impaired in aortic rings from db/db mice. Although eNOS immunostaining was not changed, that of CD141 was clearly lowered. Interestingly, diabetes-induced nitration of proteins in aorta was higher than that in the lungs. In summary, diabetes induced marked ultrastructural changes in pulmonary endothelium that were associated with the increased permeability of pulmonary microcirculation, impaired NO-dependent vascular function, with compensatory increase in PGI2 production, and increased CD141 expression. In contrast, endothelial dysfunction in the aorta was featured by impaired NO-, PGI2-dependent function and diminished CD141 expression.
- Published
- 2018
48. Corrigendum to 'European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)' [Redox Biol. 13 (2017) 94–162]
- Author
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Alina Hanf, Alberto Bindoli, Miloš Mojović, David A. Bernlohr, Yuliya Mikhed, Paula M. Brito, Agnes Görlach, João G. Costa, Vladimír Křen, Rui M. Barbosa, Jose Viña, Khrystyna Semen, María Monsalve, Opeyemi S Ademowo, Andreas Petry, Jingjing Huang, Balaraman Kalyanaraman, Ioanna Andreadou, Javier Egea, Kateryna Kubaichuk, Antonio Martínez-Ruiz, Mutay Aslan, Helen R. Griffiths, Pietro Ghezzi, S. Ilikay, Rashid Giniatullin, Melanie Hillion, Shlomo Sasson, Verónica Miguel, John F. Mulvey, Huige Li, Nuno Saraiva, Kemal Sami Korkmaz, Brandán Pedre, Isabel T.N. Nguyen, Katrin Schröder, Maria Pia Rigobello, Holger Steinbrenner, João Laranjinha, Nikoletta Papaevgeniou, Péter Ferdinandy, Kateřina Valentová, Andrew R. Pitt, Nuno G. Oliveira, Amanda J. Edson, Gratiela Gradisteanu Pircalabioru, Paul G. Winyard, Matthias Oelze, Irundika H.K. Dias, Thomas Krieg, Joris Messens, Pidder Jansen-Dürr, Vaclav Hampl, Fernando Antunes, Yves Frapart, Thierry Soldati, Bilge Debelec-Butuner, Anabela P. Rolo, Tilman Grune, Jan Vacek, Thomas Münzel, Kahina Abbas, Marina Kleanthous, Anastasia Shakirzyanova, Neven Žarković, Belma Turan, Olga Vajnerova, F. Di Lisa, Irina Milisav, Thomas Kietzmann, Rhian M. Touyz, Lidija Milkovic, Antonio Cuadrado, Pierre-Alexis Mouthuy, Serge P. Bottari, Karl-Heinz Krause, Francis Rousset, Reiko Matsui, Catarina B. Afonso, Danylo Kaminskyy, Bebiana C. Sousa, F. Van Breusegem, Ana Sofia Fernandes, Antigone Lazou, Marcus Conrad, Isabel Fabregat, Bato Korac, Pablo Hernansanz-Agustín, Aleksandra Pavićević, Jaap A. Joles, Erkan Tuncay, Fabienne Peyrot, Anikó Görbe, Sebastian Steven, Harald H.H.W. Schmidt, Martina Zatloukalová, Jan Herget, Santiago Lamas, Kari E. Fladmark, Markus Bachschmid, Afroditi Chatzi, Geoffrey L. Smith, Fulvio Ursini, Joe Dan Dunn, Kostas Tokatlidis, Rafal Koziel, Andreas Papapetropoulos, Antonio Miranda-Vizuete, Jamel El-Benna, Vincent Jaquet, B. De Smet, Vladimir R. Muzykantov, Elizabeth A. Veal, Esther Bertran, Guia Carrara, Olha Yelisyeyeva, Haike Antelmann, Ana Stancic, A. S. Yalçin, M. El Assar, Ulla G. Knaus, Marcus S. Cooke, Vsevolod V. Belousov, Leocadio Rodríguez-Mañas, Lars-Oliver Klotz, Marios Phylactides, Manuela G. López, Marie José Stasia, Tatjana Ruskovska, Stuart P. Meredith, Lokman Varisli, Niki Chondrogianni, Mahsa Karbaschi, Rainer Schulz, Henrik E. Poulsen, Andreas Daiber, Natalia Robledinos-Antón, Corinne M. Spickett, Ulrich Förstermann, Višnja Stepanić, Tamara Seredenina, Carlos M. Palmeira, Gloria Olaso-Gonzalez, Ana I. Casas, Ignacio Prieto, Gethin J. McBean, Damir Kračun, P. My-Chan Dang, Jacek Zielonka, Zoltán Giricz, and Carsten Berndt
- Subjects
0301 basic medicine ,Societies, Scientific ,Redox signaling ,International Cooperation ,Clinical Biochemistry ,Nanotechnology ,Review Article ,Biology ,Public administration ,Biochemistry ,Antioxidants ,Article ,03 medical and health sciences ,media_common.cataloged_instance ,Animals ,Humans ,Cost action ,European Union ,European union ,Molecular Biology ,lcsh:QH301-705.5 ,media_common ,Funding Agency ,Redox therapeutics ,lcsh:R5-920 ,Organic Chemistry ,Reactive nitrogen species ,030104 developmental biology ,Work (electrical) ,lcsh:Biology (General) ,Oxidative stress ,Reactive Oxygen Species ,lcsh:Medicine (General) ,Oxidation-Reduction ,Signal Transduction - Abstract
The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed., Graphical abstract fx1, Highlights • RONS are chemical mediators and a communication tool. • RONS and disturbed redox balance play a role in a broad range of diseases and aging. • Bacteria and toxins are important stimulators of cellular RONS formation. • Drugs should preserve beneficial redox signaling and inhibit detrimental RONS sources. • Redox drugs may target the origin, identity, location and time of RONS formation.
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- 2018
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49. Redox regulation of genome stability by effects on gene expression, epigenetic pathways and DNA damage/repair
- Author
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Agnes Görlach, Yuliya Mikhed, Andreas Daiber, and Ulla G. Knaus
- Subjects
Genome instability ,Redox signaling ,RNA, Untranslated ,Epigenetic regulation of neurogenesis ,DNA Repair ,HuR, mRNA-binding protein in the 3′-untranslated region ,Clinical Biochemistry ,HDAC, histone deacetylase ,Review Article ,AP-1, activator protein 1 ,Biochemistry ,Ape-1, apurinic/apyrimidinic endonuclease 1 ,GPx-1, glutathione peroxidase-1 ,Epigenesis, Genetic ,Histones ,Trx, thioredoxin ,PHD, prolylhydroxylase ,BER, base excision repair ,lcsh:QH301-705.5 ,HO-1, heme oxygenase-1 ,Epigenomics ,Genetics ,Regulation of gene expression ,Nox, member of the NADPH oxidase family ,lcsh:R5-920 ,JmjC, Jumonji C domain-containing histone demethylases ,HIF-1α, hypoxia inducible factor-1α ,5-hmC, 5-hydroxymethylcytosine ,ddc ,Cell biology ,MMP, matrix metalloproteinase ,Grx, glutaredoxin ,GAPDH, glyceraldehyde-3-phosphate dehydrogenase ,Nrf2, nuclear factor erythroid related factor 2 ,DNA methylation ,Epigenetics ,lcsh:Medicine (General) ,Oxidation-Reduction ,Signal Transduction ,5-mC, 5-methylcytosine ,DNA repair ,DNA damage ,NF-κB, nuclear factor-κB ,Biology ,Genomic Instability ,RNS, reactive nitrogen species ,ROS, reactive oxygen species ,NER, nucleotide excision repair ,SOD, superoxide dismutase ,OxyR, transcription factor (hydrogen peroxide-inducible genes activator) ,Humans ,Organic Chemistry ,PETN, pentaerithrityl tetranitrate ,Gene regulation ,Oxidative Stress ,DNMT, DNA methyltransferase ,Gene Expression Regulation ,lcsh:Biology (General) ,AREs, AU-rich elements ,HAT, histone acetyltransferase ,Keap1, kelch-like ECH-associated protein 1 ,Biomarkers ,COPD, chronic obstructive pulmonary disorder ,DNA Damage - Abstract
Reactive oxygen and nitrogen species (e.g. H2O2, nitric oxide) confer redox regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. In addition, classical regulation of gene expression or activity, including gene transcription to RNA followed by translation to the protein level, by transcription factors (e.g. NF-κB, HIF-1α) and mRNA binding proteins (e.g. GAPDH, HuR) is subject to redox regulation. This review will give an update of recent discoveries in this field, and specifically highlight the impact of reactive oxygen and nitrogen species on DNA repair systems that contribute to genomic stability. Emphasis will be placed on the emerging role of redox mechanisms regulating epigenetic pathways (e.g. miRNA, DNA methylation and histone modifications). By providing clinical correlations we discuss how oxidative stress can impact on gene regulation/activity and vise versa, how epigenetic processes, other gene regulatory mechanisms and DNA repair can influence the cellular redox state and contribute or prevent development or progression of disease., Graphical abstract, Highlights • Classical and epigenetic pathways of gene regulation are summarized. • Pathways of DNA repair are summarized. • The impact of redox signaling and oxidative stress on these pathways is discussed. • Redox regulation of mRNA stability is discussed. • New therapeutic strategies related to genome stability are presented.
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- 2015
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50. Mitochondrial Oxidative Stress, Mitochondrial DNA Damage and Their Role in Age-Related Vascular Dysfunction
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Yuliya Mikhed, Andreas Daiber, and Sebastian Steven
- Subjects
Mitochondrial ROS ,medicine.medical_specialty ,Mitochondrial DNA ,DNA Repair ,Inflammation ,Review ,Biology ,Mitochondrion ,medicine.disease_cause ,DNA, Mitochondrial ,Catalysis ,Antioxidants ,Nitric oxide ,Inorganic Chemistry ,lcsh:Chemistry ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Endothelial dysfunction ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,chemistry.chemical_classification ,Reactive oxygen species ,mitochondrial oxidative stress ,Organic Chemistry ,aging ,mitochondrial DNA damage ,General Medicine ,vascular dysfunction ,medicine.disease ,Computer Science Applications ,Mitochondria ,Oxidative Stress ,Endocrinology ,Biochemistry ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cardiovascular Diseases ,medicine.symptom ,Reactive Oxygen Species ,Oxidative stress ,DNA Damage - Abstract
The prevalence of cardiovascular diseases is significantly increased in the older population. Risk factors and predictors of future cardiovascular events such as hypertension, atherosclerosis, or diabetes are observed with higher frequency in elderly individuals. A major determinant of vascular aging is endothelial dysfunction, characterized by impaired endothelium-dependent signaling processes. Increased production of reactive oxygen species (ROS) leads to oxidative stress, loss of nitric oxide (•NO) signaling, loss of endothelial barrier function and infiltration of leukocytes to the vascular wall, explaining the low-grade inflammation characteristic for the aged vasculature. We here discuss the importance of different sources of ROS for vascular aging and their contribution to the increased cardiovascular risk in the elderly population with special emphasis on mitochondrial ROS formation and oxidative damage of mitochondrial DNA. Also the interaction (crosstalk) of mitochondria with nicotinamide adenosine dinucleotide phosphate (NADPH) oxidases is highlighted. Current concepts of vascular aging, consequences for the development of cardiovascular events and the particular role of ROS are evaluated on the basis of cell culture experiments, animal studies and clinical trials. Present data point to a more important role of oxidative stress for the maximal healthspan (healthy aging) than for the maximal lifespan.
- Published
- 2015
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