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2. The Urban Environment and Cardiometabolic Health

Author

Rajagopalan, Sanjay, Vergara-Martel, Armando, Zhong, Jeffrey, Khraishah, Haitham, Kosiborod, Mikhail, Neeland, Ian J., Dazard, Jean-Eudes, Chen, Zhuo, Munzel, Thomas, Brook, Robert D., Nieuwenhuijsen, Mark, Hovmand, Peter, and Al-Kindi, Sadeer

Published
2024
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3. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Ilaria, Gandin, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth JF, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thomas, Mitchell, Braxton D, Munzel, Thomas, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcus, and Ferrucci, Luigi

Subjects
Biological Sciences, Genetics, Human Genome, Heart Disease, Biotechnology, Cardiovascular, Aetiology, 2.1 Biological and endogenous factors, Atrial Function, Atrioventricular Node, Electrocardiography, Electrophysiological Phenomena, Female, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Mutation, Missense, Risk Factors
Abstract

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

Published
2018

4. Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-[beta]1- driven fibrotic remodeling in ischemic heart failure

Author

Garlapati, Venkata, Molitor, Michael, Michna, Thomas, Harms, Gregory S., Finger, Stefanie, Jung, Rebecca, Lagrange, Jeremy, Efentakis, Panagiotis, Wild, Johannes, Knorr, Maike, Karbach, Susanne, Wild, Sabine, Vujacic-Mirski, Ksenija, Munzel, Thomas, Daiber, Andreas, Brandt, Moritz, Gori, Tommaso, Milting, Hendrik, Tenzer, Stefan, Ruf, Wolfram, and Wenzel, Philip

Subjects
Drug therapy, Development and progression, Research, Health aspects, Heart failure -- Development and progression -- Drug therapy, Cardiovascular research, Bone marrow cells -- Health aspects, Myocardial ischemia -- Development and progression -- Drug therapy, Mitogen-activated protein kinases -- Health aspects, Transforming growth factors -- Health aspects, Coagulation -- Research, Cellular signal transduction -- Research, Fibrosis -- Development and progression -- Drug therapy
Abstract

Introduction Proper wound healing depends on effective hemostasis, which allows regeneration and reconstitution of defective tissue function (1). Coronary thrombosis causing myocardial infarction (MI) (2) leads to irreversible tissue injury, [...], Despite major advances in acute interventions for myocardial infarction (MI), adverse cardiac remodeling and excess fibrosis after MI causing ischemic heart failure (IHF) remain a leading cause of death worldwide. Here we identify a profibrotic coagulation signaling pathway that can be targeted for improved cardiac function following MI with persistent ischemia. Quantitative phosphoproteomics of cardiac tissue revealed an upregulated mitogen-activated protein kinase (MAPK) pathway in human IHF. Intervention in this pathway with trametinib improves myocardial function and prevents fibrotic remodeling in a murine model of non-reperfused MI. MAPK activation in MI requires myeloid cell signaling of protease-activated receptor 2 linked to the cytoplasmic domain of the coagulation initiator tissue factor (TF). They act upstream of pro-oxidant NOX2 NADPH oxidase, ERK1/2 phosphorylation, and activation of profibrotic TGF-[beta]1. Specific targeting with the TF inhibitor nematode anticoagulant protein c2 (NAPc2) starting 1 day after established experimental MI averts IHF. Increased TF cytoplasmic domain phosphorylation in circulating monocytes from patients with subacute MI identifies a potential thromboinflammatory biomarker reflective of increased risk for IHF and suitable for patient selection to receive targeted TF inhibition therapy.

Published
2023
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5. Clinical, Angiographic, and Procedural Correlates of Very Late Absorb Scaffold Thrombosis: Multistudy Registry Results

Author

Ellis, Stephen G., Gori, Tommaso, Serruys, Patrick W., Nef, Holger, Steffenino, Giuseppe, Brugaletta, Salvatore, Munzel, Thomas, Feliz, Cordula, Schmidt, Götz, Sabaté, Manel, Onuma, Yoshinobu, van Geuns, R.J., Gao, Run-Lin, Menichelli, Maurizio, Kereiakes, Dean J., Stone, Gregg W., Testa, Luca, Kimura, Takeshi, and Abizaid, Alexandre

Published
2018
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8. Long-Term Exposure to Transportation Noise and Risk for Type 2 Diabetes in a Nationwide Cohort Study from Denmark

Author

Thacher, Jesse D., Poulsen, Aslak H., Hvidtfeldt, Vila A., Raaschou-Nielsen, Ole, Brandt, Jorgen, Geels, Camilla, Khan, Jibran, Munzel, Thomas, and Sorensen, Mette

Subjects
Risk factors, Environmental aspects, Health aspects, Type 2 diabetes -- Risk factors -- Environmental aspects, Traffic noise -- Health aspects
Abstract

Introduction Over the past decade, a growing number of studies have linked exposure to transportation noise with increased morbidity and mortality, particularly cardiovascular health effects (Kempen et al. 2018; Munzel [...], Background: Epidemiologic studies have linked transportation noise to increased morbidity and mortality, particularly for cardiovascular outcomes. However, studies investigating metabolic outcomes such as diabetes are limited and have focused only on noise exposures estimated for the loudest residential facade. Objectives: We aimed to examine the influence of long-term residential exposure to transportation noise at the loudest and quietest residential facades and the risk for type 2 diabetes. Methods: Road traffic and railway noise exposures (Lden) at the most and least exposed facades were estimated for all dwellings in Denmark during 1990-2017. Aircraft noise was estimated in 5-dB categories. Ten-year time-weighted mean noise exposures were estimated for 3.56 million individuals [greater than or equal to] 35 years of age. From 2000 to 2017, 233,912 incident cases of type 2 diabetes were identified using hospital and prescription registries, with a mean follow-up of 12.9 y. We used Cox proportional hazards models adjusting for individual- and area-level covariates and long-term residential air pollution. The population-attributable fraction (PAF) was also computed. Results: Hazard ratios (HRs) and 95% confidence intervals (CIs) for type 2 diabetes in association with 10-dB increases in 10-y mean road traffic noise at the most and least exposed facades, respectively, were 1.05 (95% CI: 1.04, 1.05) and 1.09 (95% CI: 1.08, 1.10). Following subsequent adjustment for fine particulate matter [particulate matter [less than or equal to] 2.5 [micro]m in aerodynamic diameter] (10-y mean), the HRs (CIs) were 1.03 (95% CI: 1.03, 1.04) and 1.08 (95% CI: 1.07, 1.09), respectively. For railway noise, the HRs per 10-dB increase in 10-y mean exposure were 1.03 (95% CI: 1.02, 1.04) and 1.02 (95% CI: 1.01, 1.04) for the most and least exposed facades, respectively. Categorical models supported a linear exposure-outcome relationship for road traffic noise and, to a lesser extent, for railway noise. Aircraft noise >45 dB was associated with a 1-4% higher likelihood of type 2 diabetes compared with those who were unexposed. We found road traffic and railway noise associated with a PAF of 8.5% and 1.4%, respectively, of the diabetes cases. Discussion: Long-term exposure to road, railway, and possibly aircraft traffic noise was associated with an increased risk of type 2 diabetes in a nationwide cohort of Danish adults. Our findings suggest that diabetes should be included when estimating the burden of disease due to transportation noise.

Published
2021
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12. TNF-alpha blockade may lead to improvement of vascular function in psoriasis patients

Author

Wegner, Joanna, Karbach, Susanne, Drosos, Ioannis, Schnorbus, Boris, Muxel, Selina, Schmidt, Frank, Wenzel, Philip, Waisman, Ari, Munzel, Thomas, Gori, Tommaso, von Stebut, Esther, Wegner, Joanna, Karbach, Susanne, Drosos, Ioannis, Schnorbus, Boris, Muxel, Selina, Schmidt, Frank, Wenzel, Philip, Waisman, Ari, Munzel, Thomas, Gori, Tommaso, and von Stebut, Esther

Abstract

Psoriasis is one of the most common chronic inflammatory skin diseases and at the same time a risk factor for cardiovascular disease. Interleukin-17A (IL-17A)-mediated inflammation in psoriasis may lead to vascular dysfunction. This study aimed at investigating whether anti-inflammatory treatment by tumor necrosis factor (TNF)-alpha blockade alters vascular function in psoriasis patients. A total of 11 patients with psoriasis who underwent treatment with either adalimumab (n = 8) or etanercept (n = 3), 10 healthy control individuals and 14 patients with coronary artery disease (CAD) were included in this study. Treatment response was assessed using the Psoriasis Area and Severity Index (PASI) score. Endothelial reactivity and resting endothelium-dependent vascular tone were assessed by ultrasound measurement of flow-mediated dilation (FMD) and low-flow-mediated constriction (l-FMC), respectively. FMD was slightly impaired in psoriasis patients compared to healthy controls. Anti-TNF-alpha treatment did not significantly change FMD levels. Psoriasis patients showed a trend towards increased baseline vascular activity compared to healthy controls. Anti-TNF-alpha treatment significantly improved l-FMC in psoriasis patients. Noteworthy, both FMD and l-FMC in psoriasis patients were comparable to those in patients with CAD; however, an important influence of age differences between the groups or co-existent classical cardiovascular risk factors on FMD and l-FMC cannot be ruled out by our small study. The results suggest that anti-inflammatory treatment with TNF-alpha blockade improves vascular function in patients with psoriasis, mainly by altering baseline vascular tone. Further studies will be necessary to establish the potentially protective impact of anti-inflammatory therapy on vascular function in patients with chronic inflammatory diseases.

Published
2022

29. [YIA] Myeloid cell derived Interleukin-6 causes vascular dysfunction, inflammation and endothelin-1 expression in mice

Author

Wild, Johannes, Knopp, Tanja, Jung, Rebecca, Efentakis, Panagiotis, Bochenek, Magdalena, Masri, Joumana, Randriamboavonjy, Voahanginirina, Wunderlich, Thomas, Oelze, Matthias, Daiber, Andreas, Bosmann, Markus, Afer, Kathrin Sch, Fleming, Ingrid, Munzel, Thomas, Philip Wenzel, Waisman, Ari, and Karbach, Susanne

Subjects
Physiology (medical), Biochemistry
Published
2022
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32. A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1

Author

Morange, Pierre-Emmanuel, Bezemer, Irene, Saut, Noemie, Bare, Lance, Burgos, Gwenaelle, Brocheton, Jessy, Durand, Herve, Biron-Andreani, Christine, Schved, Jean-Francois, Pernod, Gilles, Galan, Pilar, Drouet, Ludovic, Zelenika, Diana, Germain, Marine, Nicaud, Viviane, Heath, Simon, Ninio, Ewa, Delluc, Aurelien, Munzel, Thomas, Zeller, Tanja, Brand-Herrmann, Stefan-Martin, Alessi, Marie-Christine, Tiret, Laurence, Lathrop, Mark, Cambien, Francois, Blankenberg, Stefan, Emmerich, Joseph, Tregouet, David-Alexandre, and Rosendaal, Frits R.

Subjects
Human genome -- Research, Single nucleotide polymorphisms -- Analysis, Genetic transcription -- Analysis, Venous thrombosis -- Genetic aspects, Biological sciences
Abstract

A multistage strategy was used to obtain strong evidence for implication of the HIVEP1 locus as a candidate for venous thrombosis (VT) risk. The results provide first evidence for the role of a genetic variant on the risk of VT outside the traditional coagulation/fibrinolysis cascade.

Published
2010

34. Sensitive troponin I assay in ear diagnosis of acute myocardial infarction

Author

Keller, Till, Zeller, Tanja, Peetz, Dirk, Tzikas, Stergios, Roth, Alexander, Czyz, Ewa, Bickel, Christoph, Baldus, Stephan, Warnholtz, Ascan, Frohlich, Meike, Sinning, Christoph R., Eleftheriadis, Medea S., Wild, Philipp S., Schnabel, Renate B., Lubos, Edith, Jachmann, Nicole, Genth-Zotz, Sabine, Post, Felix, Nicaud, Viviane, Tiret, Laurence, Lackner, Karl J., Munzel, Thomas F., and Blankenberg, Stefan

Subjects
Heart attack -- Diagnosis
Abstract

A study was conducted to evaluate whether the use of sensitive troponin I assay was useful in the early diagnosis and risk ratification of acute myocardial infarction. Results indicated that sensitive troponin I was very effective in the diagnosis, regardless of chest-pain onset.

Published
2009

35. Genetic variants associated with cardiac structure and function

Author

Vasan, Ramachandran S., Glazer, Nicole L., Felix, Janine F., Lieb, Wolfgang, Wild, Philipp S., Felix, Stephan B, Watzinger, Norbert, Larson, Martin G., Smith, Nicholas L., Dehghan, Abbas, Gro-henning, Anika, Schillert, Arne, Teumer, Alexander, Schmidt, Reinhold, Kathiresan, Sekar, Lumley, Thomas, Aulchenko, Yurii S., Konig, Inke R., Zeller, Tanja, Homuth, Georg, Struchalin, Maksim, Aragam, Jayashri, Bis, Joshua C., Rivadeneira, Fernando, Erdmann, Jeanette, Schnabel, Renate B., Dorr, Marcus, Zweiker, Robert, Lind Lars, Rodeheffer, Richard J., Greiser, Karin Halina, Levy, Daniel, Haritunians, Talin, Deckers, Jaap W., Stritzke, Jan, Lackner, Karl J., Volker, Uwe, Ingelsson, Erik, Kullo, Iftikhar, Haerting, Johannes, OEDonnell, Christopher J., Heckbert, Susan R., Stricker, Bruno H., Ziegler, Andreas, Reffelmann, Thorsten, Redfield, Margaret M., Werdan, Karl, Mitchell, Gary F., Rice, Kenneth, Arnett, Donna K., Hofman, Albert, Gottdiener, John S., Uitterlinden, Andre G., Meitinger, Thomas, Blettner, Maria, Friedrich, Nele, Wang, Thomas J., Psaty, Bruce M., van Duijn, Cornelia M., Wichmann, H.-Erich, Munzel, Thomas F., Kroemer, Heyo K., Benjamin, Emelia J., Rotter, Jerome I., Witteman, Jacqueline C., Schunkert, Heribert, Schmidt, Helena, Volzke, Henry, and Blankenberg, Stefan

Subjects
Cardiovascular diseases -- Genetic aspects, Echocardiography -- Usage, Heart -- Physiological aspects, Heart -- Genetic aspects, Meta-analysis -- Usage
Abstract

A study was conducted to investigate and identify genetic variants that are associated with cardiac structure and function through a meta-analysis. Results indicated that there were 5 genetic loci, associated with variance in cardiac dimensions and aortic root size; however, the proportion of variance is quite small.

Published
2009

44. Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins

Author

Lau, Denise, Mollnau, Hanke, Eiserich, Jason P., Freeman, Bruce A., Daiber, Andreas, Gehling, Ursula M., Brummer, Jens, Rudolph, Volker, Munzel, Thomas, Heitzer, Thomas, Meinertz, Thomas, and Baldus, Stephan

Subjects
Leukocytes -- Research, Endothelium -- Research, Cytokines -- Research, Atherosclerosis -- Research, Science and technology
Abstract

Recruitment and activation of polymorphonuclear neutrophils (PMNs) reflects a primary immunological response to invading pathogens and has also emerged as a hallmark of vascular inflammation. One of the principal enzymes released upon PMN activation is myeloperoxidase (MPO), a heme protein that not only generates cytotoxic oxidants but also impacts deleteriously on nitric oxide-dependent signaling cascades within the vasculature. Because MPO also associates with the membrane of PMN, we evaluated whether MPO could also function as an autocrine modulator of PMN activation. The extent of PMN membrane-associated MPO was elevated in patients with acute inflammatory vascular disease compared with healthy individuals. Isolated PMNs bound free MPO by a CD11b/CD18 integrin-dependent mechanism. PMNs exposed to MPO were characterized by increased tyrosine phosphorylation and p38 mitogen-activated protein kinase activation. Also, nuclear translocation of NF[kappa]B in PMN was enhanced after incubation with MPO, as was surface expression of CD11b. Binding of PMN to MPO-coated fibronectin surfaces amplified PMN degranulation, as evidenced by increased release of MPO and elastase. MPO also augmented PMN-dependent superoxide ([O.sup.*-.sub.2]) production, which was prevented by anti-CD11b antibodies, but not MPO inhibitors. Collectively, these results reveal that binding of MPO to CD11b/CD18 integrins stimulates PMN signaling pathways to induce PMN activation in a mechanism independent of MPO catalytic activity. These cytokine-like properties of MPO thus represent an additional dimension of the proinflammatory actions of MPO in vascular disease. atherosclerosis | cytokine | endothelium | leukocyte | nitric oxide

Published
2005

45. Lese-Launen

Author

Friedhelm Munzel, Thomas Nisslmüller and Friedhelm Munzel, Thomas Nisslmüller

Abstract

Bert Brecht hat das Lesen als'Lebens-Mittel'bezeichnet. In der Pandemie hat viele Menschen die Lust am Lesen gepackt. So gründen u.a. Prominente digitale Buch-Clubs, tauschen Lesetipps aus. Die Autoren stellen in diesem Buch auf je individuelle Weise vor, was Lesen für sie selbst bedeutet, wie faszinierend manche Bücher sind und wie Lesen unser aller Leben bereichert und vertieft - auch in Auseinandersetzung mit der Digitalisierung. Lesen stärkt das Selbstbewusstsein, fordert heraus und stiftet Heil: Denn im lesenden Lauschen auf Heilsames gewinnt die Seele Kraft und unser Herz Mut, dem Leben standzuhalten.

Published
2022

46. Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia

Author

Reiner, Alexander P., Hartiala, Jaana, Zeller, Tanja, Bis, Joshua C., Dupuis, Josée, Fornage, Myriam, Baumert, Jens, Kleber, Marcus E., Wild, Philipp S., Baldus, Stephan, Bielinski, Suzette J., Fontes, João D., Illig, Thomas, Keating, Brendan J., Lange, Leslie A., Ojeda, Francisco, Müller-Nurasyid, Martina, Munzel, Thomas F., Psaty, Bruce M., Rice, Kenneth, Rotter, Jerome I., Schnabel, Renate B., Tang, W.H. Wilson, Thorand, Barbara, Erdmann, Jeanette, Consortium, CARDIoGRAM, Jacobs, David R., Jr, Wilson, James G., Koenig, Wolfgang, Tracy, Russell P., Blankenberg, Stefan, März, Winfried, Gross, Myron D., Benjamin, Emelia J., Hazen, Stanley L., and Allayee, Hooman

Published
2013
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48. Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

Author

Davison, Lucy J., Wallace, Chris, Cooper, Jason D., Cope, Nathan F., Wilson, Nicola K., Smyth, Deborah J., Howson, Joanna M.M., Saleh, Nada, Al-Jeffery, Abdullah, Angus, Karen L., Stevens, Helen E., Nutland, Sarah, Duley, Simon, Coulson, Richard M.R., Walker, Neil M., Burren, Oliver S., Rice, Catherine M., Cambien, Francois, Zeller, Tanja, Munzel, Thomas, Lackner, Karl, Blankenberg, Stefan, Fraser, Peter, Gottgens, Berthold, and Todd, John A.

Published
2012
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50. Vascular dysfunction in experimental diabetes is improved by pentaerithrityl tetranitrate but not isosorbide-5-mononitrate therapy

Author

Schuhmacher, Swenja, Oelze, Matthias, Bollmann, Franziska, Kleinert, Hartmut, Otto, Christian, Heeren, Tjebo, Steven, Sebastian, Hausding, Michael, Knorr, Maike, Pautz, Andrea, Reifenberg, Kurt, Schulz, Eberhard, Gori, Tommaso, Wenzel, Philip, Munzel, Thomas, and Daiber, and Andreas

Subjects
Care and treatment, Prevention, Complications and side effects, Physiological aspects, Research, Risk factors, Diabetes mellitus -- Research -- Complications and side effects -- Care and treatment, Antioxidants (Nutrients) -- Physiological aspects -- Research, Cardiovascular diseases -- Risk factors -- Prevention -- Research, Diabetes -- Research -- Complications and side effects -- Care and treatment, Antioxidants -- Physiological aspects -- Research
Abstract

Diabetes is a major risk factor for the development of cardiovascular disease (1), and endothelial dysfunction is encountered early during the development of vascular complications in this setting (2). Animal [...], OBJECTIVE--Diabetes is associated with vascular oxidative stress, activation of NADPH oxidase, and uncoupling of nitric oxide (NO) synthase (endothelial NO synthase [eNOS]). Pentaerithrityl tetranitrate (PETN) is an organic nitrate with potent antioxidant properties via induction of heme oxygenase-1 (HO-1). We tested whether treatment with PETN improves vascular dysfunction in the setting of experimental diabetes. RESEARCH DESIGN AND METHODS--After induction of hyperglycemia by streptozotocin (STZ) injection (60 mg/kg i.v.), PETN (15 mg/kg/day p.o.) or isosorbide-5-mononitrate (ISMN; 75 mg/kg/day p.o.) was fed to Wistar rats for 7 weeks. Oxidative stress was assessed by optical methods and oxidative protein modifications, vascular function was determined by isometric tension recordings, protein expression was measured by Western blotting, RNA expression was assessed by quantitative RT-PCR, and HO-1 promoter activity in stable transfected cells was determined by luciferase assays. RESULTS--PETN, but not ISMN, improved endothelial dysfunction. NADPH oxidase and serum xanthine oxidase activities were significantly reduced by PETN but not by ISMN. Both organic nitrates had minor effects on the expression of NADPH oxidase subunits, eNOS and dihydrofolate reductase (Western blotting). PETN, but not ISMN, normalized the expression of GTP cyclohydrolase-1, extracellular superoxide dismutase, and S-glutathionylation of eNOS, thereby preventing eNOS uncoupling. The expression of the antioxidant enzyme, HO-1, was increased by STZ treatment and further upregulated by PETN, but not ISMN, via activation of the transcription factor NRF2. CONCLUSIONS--In contrast to ISMN, the organic nitrate, PETN, improves endothelial dysfunction in diabetes by preventing eNOS uncoupling and NADPH oxidase activation, thereby reducing oxidative stress. Thus, PETN therapy may be suited to treat patients with cardiovascular complications of diabetes. Diabetes 60:2608-2616, 2011

Published
2011
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