96 results on '"Zhang, You-Yi"'
Search Results
2. Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy.
- Author
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Vendrov AE, Xiao H, Lozhkin A, Hayami T, Hu G, Brody MJ, Sadoshima J, Zhang YY, Runge MS, and Madamanchi NR
- Subjects
- Animals, Mice, Fibrosis, Hydrogen Peroxide metabolism, Inflammation metabolism, NADPH Oxidase 4 genetics, NADPH Oxidase 4 metabolism, NADPH Oxidases metabolism, Reactive Oxygen Species metabolism, Myocytes, Cardiac metabolism, Takotsubo Cardiomyopathy metabolism, Takotsubo Cardiomyopathy pathology
- Abstract
In acute sympathetic stress, catecholamine overload can lead to stress cardiomyopathy. We tested the hypothesis that cardiomyocyte NOX4 (NADPH oxidase 4)-dependent mitochondrial oxidative stress mediates inflammation and diastolic dysfunction in stress cardiomyopathy. Isoproterenol (ISO; 5 mg/kg) injection induced sympathetic stress in wild-type and cardiomyocyte (CM)-specific Nox4 knockout (Nox4
CM-/- ) mice. Wild-type mice treated with ISO showed higher CM NOX4 expression, H2 O2 levels, inflammasome activation, and IL18, IL6, CCL2, and TNFα levels than Nox4CM-/- mice. Spectral flow cytometry and t-SNE analysis of cardiac cell suspensions showed significant increases in pro-inflammatory and pro-fibrotic embryonic-derived resident (CCR2- MHCIIhi CX3CR1hi ) macrophages in wild-type mice 3 days after ISO treatment, whereas Nox4CM-/- mice had a higher proportion of embryonic-derived resident tissue-repair (CCR2- MHCIIlo CX3CR1lo ) macrophages. A significant increase in cardiac fibroblast activation and interstitial collagen deposition and a restrictive pattern of diastolic dysfunction with increased filling pressure was observed in wild-type hearts compared with Nox4CM-/- 7 days post-ISO. A selective NOX4 inhibitor, GKT137831, reduced myocardial mitochondrial ROS, macrophage infiltration, and fibrosis in ISO-injected wild-type mice, and preserved diastolic function. Our data suggest sympathetic overstimulation induces resident macrophage (CCR2- MHCII+ ) activation and myocardial inflammation, resulting in fibrosis and impaired diastolic function mediated by CM NOX4-dependent ROS., Competing Interests: Declaration of competing interest Marschall S. Runge is a member of the Board of Directors at Eli Lilly and Company. Other authors have declared that no conflict of interest exists., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
3. Dual-omics reveals temporal differences in acute sympathetic stress-induced cardiac inflammation following α 1 and β-adrenergic receptors activation.
- Author
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Zhang D, Zhao MM, Wu JM, Wang R, Xue G, Xue YB, Shao JQ, Zhang YY, Dong ED, Li ZY, and Xiao H
- Subjects
- Animals, Mice, Heart, Arrhythmias, Cardiac, Inflammation metabolism, Receptors, Adrenergic, alpha-1 genetics, Receptors, Adrenergic, alpha-1 metabolism, Receptors, Adrenergic, beta genetics, Receptors, Adrenergic, beta metabolism, Cardiovascular Diseases
- Abstract
Sympathetic stress is prevalent in cardiovascular diseases. Sympathetic overactivation under strong acute stresses triggers acute cardiovascular events including myocardial infarction (MI), sudden cardiac death, and stress cardiomyopathy. α
1 -ARs and β-ARs, two dominant subtypes of adrenergic receptors in the heart, play a significant role in the physiological and pathologic regulation of these processes. However, little is known about the functional similarities and differences between α1 - and β-ARs activated temporal responses in stress-induced cardiac pathology. In this work, we systematically compared the cardiac temporal genome-wide profiles of acute α1 -AR and β-AR activation in the mice model by integrating transcriptome and proteome. We found that α1 - and β-AR activations induced sustained and transient inflammatory gene expression, respectively. Particularly, the overactivation of α1 -AR but not β-AR led to neutrophil infiltration at one day, which was closely associated with the up-regulation of chemokines, activation of NF-κB pathway, and sustained inflammatory response. Furthermore, there are more metabolic disorders under α1 -AR overactivation compared with β-AR overactivation. These findings provide a new therapeutic strategy that, besides using β-blocker as soon as possible, blocking α1 -AR within one day should also be considered in the treatment of acute stress-associated cardiovascular diseases., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)- Published
- 2023
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4. IMM-H007 attenuates isoprenaline-induced cardiac fibrosis through targeting TGFβ1 signaling pathway.
- Author
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Wang SX, Feng YN, Feng S, Wu JM, Zhang M, Xu WL, Zhang YY, Zhu HB, Xiao H, and Dong ED
- Subjects
- Actins metabolism, Adenosine analogs & derivatives, Adenosine pharmacology, Animals, Collagen, Fibrosis, Isoproterenol toxicity, Mice, Molecular Docking Simulation, Receptors, Adrenergic, beta, Signal Transduction, AMP-Activated Protein Kinases metabolism, Transforming Growth Factor beta1 metabolism
- Abstract
Upon chronic stress, β-adrenergic receptor activation induces cardiac fibrosis and leads to heart failure. The small molecule compound IMM-H007 has demonstrated protective effects in cardiovascular diseases via activation of AMP-activated protein kinase (AMPK). This study aimed to investigate IMM-H007 effects on cardiac fibrosis induced by β-adrenergic receptor activation. Because adenosine analogs also exert AMPK-independent effects, we assessed AMPK-dependent and -independent IMM-H007 effects in murine models of cardiac fibrosis. Continual subcutaneous injection of isoprenaline for 7 days caused cardiac fibrosis and cardiac dysfunction in mice in vivo. IMM-H007 attenuated isoprenaline-induced cardiac fibrosis, diastolic dysfunction, α-smooth muscle actin expression, and collagen I deposition in both wild-type and AMPKα2
-/- mice. Moreover, IMM-H007 inhibited transforming growth factor β1 (TGFβ1) expression in wild-type, but not AMPKα2-/- mice. By contrast, IMM-H007 inhibited Smad2/3 signaling downstream of TGFβ1 in both wild-type and AMPKα2-/- mice. Surface plasmon resonance and molecular docking experiments showed that IMM-H007 directly interacts with TGFβ1, inhibits its binding to TGFβ type II receptors, and downregulates the Smad2/3 signaling pathway downstream of TGFβ1. These findings suggest that IMM-H007 inhibits isoprenaline-induced cardiac fibrosis via both AMPKα2-dependent and -independent mechanisms. IMM-H007 may be useful as a novel TGFβ1 antagonist., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)- Published
- 2022
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5. Glibenclamide alleviates β adrenergic receptor activation-induced cardiac inflammation.
- Author
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Cao N, Wang JJ, Wu JM, Xu WL, Wang R, Chen XD, Feng YN, Cong WW, Zhang YY, Xiao H, and Dong ED
- Subjects
- Animals, Arrhythmias, Cardiac, Glyburide pharmacology, Inflammation chemically induced, Inflammation drug therapy, Inflammation metabolism, Isoproterenol pharmacology, Male, Mice, Mice, Inbred C57BL, Myocytes, Cardiac, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Potassium metabolism, Potassium pharmacology, Reactive Oxygen Species metabolism, Inflammasomes metabolism, Receptors, Adrenergic, beta metabolism
- Abstract
β-Adrenergic receptor (β-AR) overactivation is a major pathological factor associated with cardiac diseases and mediates cardiac inflammatory injury. Glibenclamide has shown anti-inflammatory effects in previous research. However, it is unclear whether and how glibenclamide can alleviate cardiac inflammatory injury induced by β-AR overactivation. In the present study, male C57BL/6J mice were treated with or without the β-AR agonist isoprenaline (ISO) with or without glibenclamide pretreatment. The results indicated that glibenclamide alleviated ISO-induced macrophage infiltration in the heart, as determined by Mac-3 staining. Consistent with this finding, glibenclamide also inhibited ISO-induced chemokines and proinflammatory cytokines expression in the heart. Moreover, glibenclamide inhibited ISO-induced cardiac fibrosis and dysfunction in mice. To reveal the protective mechanism of glibenclamide, the NLRP3 inflammasome was further analysed. ISO activated the NLRP3 inflammasome in both cardiomyocytes and mouse hearts, but this effect was alleviated by glibenclamide pretreatment. Furthermore, in cardiomyocytes, ISO increased the efflux of potassium and the generation of ROS, which are recognized as activators of the NLRP3 inflammasome. The ISO-induced increases in these processes were inhibited by glibenclamide pretreatment. Moreover, glibenclamide inhibited the cAMP/PKA signalling pathway, which is downstream of β-AR, by increasing phosphodiesterase activity in mouse hearts and cardiomyocytes. In conclusion, glibenclamide alleviates β-AR overactivation-induced cardiac inflammation by inhibiting the NLRP3 inflammasome. The underlying mechanism involves glibenclamide-mediated suppression of potassium efflux and ROS generation by inhibiting the cAMP/PKA pathway., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)
- Published
- 2022
- Full Text
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6. Small molecule QF84139 ameliorates cardiac hypertrophy via activating the AMPK signaling pathway.
- Author
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Li XX, Zhang P, Yang Y, Wang JJ, Zheng YJ, Tan JL, Liu SY, Yan YM, Zhang YY, Cheng YX, and Yang HT
- Subjects
- Animals, Animals, Newborn, Aorta drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Male, Mice, Mice, Inbred C57BL, Organ Size drug effects, Phenylephrine pharmacology, RNA, Small Interfering pharmacology, Rats, Rats, Sprague-Dawley, Signal Transduction drug effects, AMP-Activated Protein Kinases drug effects, Cardiomegaly pathology, Myocytes, Cardiac drug effects
- Abstract
Cardiac hypertrophy is a common adaptive response to a variety of stimuli, but prolonged hypertrophy leads to heart failure. Hence, discovery of agents treating cardiac hypertrophy is urgently needed. In the present study, we investigated the effects of QF84139, a newly synthesized pyrazine derivative, on cardiac hypertrophy and the underlying mechanisms. In neonatal rat cardiomyocytes (NRCMs), pretreatment with QF84139 (1-10 μM) concentration-dependently inhibited phenylephrine-induced hypertrophic responses characterized by fetal genes reactivation, increased ANP protein level and enlarged cardiomyocytes. In adult male mice, administration of QF84139 (5-90 mg·kg
-1 ·d-1 , i.p., for 2 weeks) dose-dependently reversed transverse aortic constriction (TAC)-induced cardiac hypertrophy displayed by cardiomyocyte size, left ventricular mass, heart weights, and reactivation of fetal genes. We further revealed that QF84139 selectively activated the AMPK signaling pathway without affecting the phosphorylation of CaMKIIδ, ERK1/2, AKT, PKCε, and P38 kinases in phenylephrine-treated NRCMs and in the hearts of TAC-treated mice. In NRCMs, QF84139 did not show additive effects with metformin on the AMPK activation, whereas the anti-hypertrophic effect of QF84139 was abolished by an AMPK inhibitor Compound C or knockdown of AMPKα2. In AMPKα2-deficient mice, the anti-hypertrophic effect of QF84139 was also vanished. These results demonstrate that QF84139 attenuates the PE- and TAC-induced cardiac hypertrophy via activating the AMPK signaling. This structurally novel compound would be a promising lead compound for developing effective agents for the treatment of cardiac hypertrophy., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)- Published
- 2022
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7. Novel roles of an intragenic G-quadruplex in controlling microRNA expression and cardiac function.
- Author
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Zhu M, Gao J, Lin XJ, Gong YY, Qi YC, Ma YL, Song YX, Tan W, Li FY, Ye M, Gong J, Cui QH, Huang ZH, Zhang YY, Wang XJ, Lan F, Wang SQ, Yuan G, Feng Y, and Xu M
- Subjects
- Animals, Benzylisoquinolines pharmacology, CRISPR-Cas Systems, Cells, Cultured, Gene Expression Regulation, Myocardium metabolism, Myocytes, Cardiac physiology, RNA Processing, Post-Transcriptional, RNA-Binding Proteins metabolism, Rats, Rats, Sprague-Dawley, Ribonuclease III metabolism, Ryanodine Receptor Calcium Release Channel metabolism, G-Quadruplexes drug effects, MicroRNAs chemistry, MicroRNAs metabolism, Myocardial Contraction genetics, Myocytes, Cardiac metabolism
- Abstract
Simultaneous dysregulation of multiple microRNAs (miRs) affects various pathological pathways related to cardiac failure. In addition to being potential cardiac disease-specific markers, miR-23b/27b/24-1 were reported to be responsible for conferring cardiac pathophysiological processes. In this study, we identified a conserved guanine-rich RNA motif within the miR-23b/27b/24-1 cluster that can form an RNA G-quadruplex (rG4) in vitro and in cells. Disruption of this intragenic rG4 significantly increased the production of all three miRs. Conversely, a G4-binding ligand tetrandrine (TET) stabilized the rG4 and suppressed miRs production in human and rodent cardiomyocytes. Our further study showed that the rG4 prevented Drosha-DGCR8 binding and processing of the pri-miR, suppressing the biogenesis of all three miRs. Moreover, CRISPR/Cas9-mediated G4 deletion in the rat genome aberrantly elevated all three miRs in the heart in vivo, leading to cardiac contractile dysfunction. Importantly, loss of the G4 resulted in reduced targets for the aforementioned miRs critical for normal heart function and defects in the L-type Ca2+ channel-ryanodine receptor (LCC-RyR) coupling in cardiomyocytes. Our results reveal a novel mechanism for G4-dependent regulation of miR biogenesis, which is essential for maintaining normal heart function., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2021
- Full Text
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8. Membrane nanotubes facilitate the propagation of inflammatory injury in the heart upon overactivation of the β-adrenergic receptor.
- Author
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Shen J, Wu JM, Hu GM, Li MZ, Cong WW, Feng YN, Wang SX, Li ZJ, Xu M, Dong ED, Zhang YY, and Xiao H
- Subjects
- Adrenergic beta-Agonists pharmacology, Animals, Animals, Newborn, Cell Membrane drug effects, Cell Membrane immunology, Cell Membrane metabolism, Fibroblasts drug effects, Fibroblasts immunology, Fibroblasts metabolism, Fibroblasts pathology, Inflammation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Reperfusion Injury etiology, Myocardial Reperfusion Injury metabolism, Myocytes, Cardiac drug effects, Myocytes, Cardiac immunology, Myocytes, Cardiac metabolism, Nanotubes, Pyroptosis, Cell Membrane pathology, Heart physiopathology, Isoproterenol pharmacology, Myocardial Reperfusion Injury pathology, Myocytes, Cardiac pathology, NLR Family, Pyrin Domain-Containing 3 Protein physiology, Receptors, Adrenergic, beta chemistry
- Abstract
Acute sympathetic stress quickly induces cardiac inflammation and injury, suggesting that pathogenic signals rapidly spread among cardiac cells and that cell-to-cell communication may play an important role in the subsequent cardiac injury. However, the underlying mechanism of this response is unknown. Our previous study demonstrated that acute β-adrenergic receptor (β-AR) signaling activates inflammasomes in the heart, which triggers the inflammatory cascade. In the present study, β-AR overactivation induced inflammasome activation in both the cardiomyocytes and cardiac fibroblasts (CFs) of mice hearts following a subcutaneous injection of isoproterenol (ISO, 5 mg/kg body weight), a selective agonist of β-AR. In isolated cardiac cells, ISO treatment only activated the inflammasomes in the cardiomyocytes but not the CFs. These results demonstrated that inflammasome activation was propagated from cardiomyocytes to CFs in the mice hearts. Further investigation revealed that the inflammasomes were activated in the cocultured CFs that connected with cardiomyocytes via membrane nanotubes (MNTs), a novel membrane structure that mediates distant intercellular connections and communication. Disruption of the MNTs with the microfilament polymerization inhibitor cytochalasin D (Cyto D) attenuated the inflammasome activation in the cocultured CFs. In addition, the MNT-mediated inflammasome activation in the CFs was blocked by deficiency of the inflammasome component NOD-like receptor protein 3 (NLRP3) in the cardiomyocytes, but not NLRP3 deficiency in the CFs. Moreover, ISO induced pyroptosis in the CFs cocultured with cardiomyocytes, and this process was inhibited by disruption of the MNTs with Cyto D or by the NLRP3 inhibitor MCC950 and the caspase-1 inhibitor Z-YVAD-FMK (FMK). Our study revealed that MNTs facilitate the rapid propagation of inflammasome activation among cardiac cells to promote pyroptosis in the early phase of β-adrenergic insult. Therefore, preventing inflammasome transfer is a potential therapeutic strategy to alleviate acute β-AR overactivation-induced cardiac injury.
- Published
- 2020
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9. Author Correction: Increased circulating β2-adrenergic receptor autoantibodies are associated with smoking-related emphysema.
- Author
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Hu JY, Liu BB, Du YP, Zhang Y, Zhang YW, Zhang YY, Xu M, and He B
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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10. α 1 -AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation.
- Author
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Xin JZ, Wu JM, Hu GM, Gu HJ, Feng YN, Wang SX, Cong WW, Li MZ, Xu WL, Song Y, Xiao H, Zhang YY, and Wang L
- Subjects
- Adrenergic alpha-1 Receptor Agonists pharmacology, Animals, Dose-Response Relationship, Drug, Echocardiography, Heart drug effects, Inflammasomes drug effects, Inflammation chemically induced, Inflammation pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Structure, NLR Family, Pyrin Domain-Containing 3 Protein deficiency, Phenylephrine pharmacology, Structure-Activity Relationship, Sympathetic Nervous System drug effects, Sympathetic Nervous System metabolism, Sympathetic Nervous System pathology, Inflammasomes metabolism, Inflammation metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Receptors, Adrenergic, alpha-1 metabolism
- Abstract
Acute sympathetic stress causes excessive secretion of catecholamines and induces cardiac injuries, which are mainly mediated by β-adrenergic receptors (β-ARs). However, α
1 -adrenergic receptors (α1 -ARs) are also expressed in the heart and are activated upon acute sympathetic stress. In the present study, we investigated whether α1 -AR activation induced cardiac inflammation and the underlying mechanisms. Male C57BL/6 mice were injected with a single dose of α1 -AR agonist phenylephrine (PE, 5 or 10 mg/kg, s.c.) with or without pretreatment with α-AR antagonist prazosin (5 mg/kg, s.c.). PE injection caused cardiac dysfunction and cardiac inflammation, evidenced by the increased expression of inflammatory cytokine IL-6 and chemokines MCP-1 and MCP-5, as well as macrophage infiltration in myocardium. These effects were blocked by prazosin pretreatment. Furthermore, PE injection significantly increased the expression of NOD-like receptor protein 3 (NLRP3) and the cleavage of caspase-1 (p20) and interleukin-18 in the heart; similar results were observed in both Langendorff-perfused hearts and cultured cardiomyocytes following the treatment with PE (10 μM). Moreover, PE-induced NLRP3 inflammasome activation and cardiac inflammation was blocked in Nlrp3-/- mice compared with wild-type mice. In conclusion, α1 -AR overactivation induces cardiac inflammation by activating NLRP3 inflammasomes.- Published
- 2020
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11. Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening.
- Author
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Canugovi C, Stevenson MD, Vendrov AE, Hayami T, Robidoux J, Xiao H, Zhang YY, Eitzman DT, Runge MS, and Madamanchi NR
- Subjects
- Age Factors, Animals, Aorta physiopathology, Cellular Senescence genetics, Extracellular Matrix metabolism, Gene Expression, Genetic Association Studies, Hydrogen Peroxide metabolism, Immunohistochemistry, Mice, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle metabolism, NADPH Oxidase 4 metabolism, Oxidative Stress, Reactive Oxygen Species metabolism, Superoxides metabolism, Vasculitis genetics, Vasculitis metabolism, Vasculitis pathology, Aorta metabolism, Genes, Mitochondrial, NADPH Oxidase 4 genetics, Vascular Stiffness genetics
- Abstract
Aging is characterized by increased aortic stiffness, an early, independent predictor and cause of cardiovascular disease. Oxidative stress from excess reactive oxygen species (ROS) production increases with age. Mitochondria and NADPH oxidases (NOXs) are two major sources of ROS in cardiovascular system. We showed previously that increased mitochondrial ROS levels over a lifetime induce aortic stiffening in a mouse oxidative stress model. Also, NADPH oxidase 4 (NOX4) expression and ROS levels increase with age in aortas, aortic vascular smooth muscle cells (VSMCs) and mitochondria, and are correlated with age-associated aortic stiffness in hypercholesterolemic mice. The present study investigated whether young mice (4 months-old) with increased mitochondrial NOX4 levels recapitulate vascular aging and age-associated aortic stiffness. We generated transgenic mice with low (Nox4TG605; 2.1-fold higher) and high (Nox4TG618; 4.9-fold higher) mitochondrial NOX4 expression. Young Nox4TG618 mice showed significant increase in aortic stiffness and decrease in phenylephrine-induced aortic contraction, but not Nox4TG605 mice. Increased mitochondrial oxidative stress increased intrinsic VSMC stiffness, induced aortic extracellular matrix remodeling and fibrosis, a leftward shift in stress-strain curves, decreased volume compliance and focal adhesion turnover in Nox4TG618 mice. Nox4TG618 VSMCs phenocopied other features of vascular aging such as increased DNA damage, increased premature and replicative senescence and apoptosis, increased proinflammatory protein expression and decreased respiration. Aortic stiffening in young Nox4TG618 mice was significantly blunted with mitochondrial-targeted catalase overexpression. This demonstration of the role of mitochondrial oxidative stress in aortic stiffness will galvanize search for new mitochondrial-targeted therapeutics for treatment of age-associated vascular dysfunction., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
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12. β‑estradiol alleviates hypertension‑ and concanavalin A‑mediated inflammatory responses via modulation of connexins in peripheral blood lymphocytes.
- Author
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Ni X, Zhang L, Ma X, Shan LY, Li L, Si JQ, Li XZ, Zhang YY, and Ma KT
- Subjects
- Animals, Blood Pressure drug effects, Connexin 43 genetics, Connexin 43 metabolism, Connexins genetics, Cytokines blood, Cytokines metabolism, Gap Junctions metabolism, Gene Expression, Hypertension physiopathology, Inflammation pathology, Inflammation Mediators metabolism, Kidney drug effects, Kidney metabolism, Kidney pathology, Lymphocyte Activation drug effects, Male, Rats, Vascular Remodeling drug effects, Concanavalin A adverse effects, Connexins metabolism, Estradiol pharmacology, Hypertension complications, Inflammation etiology, Inflammation metabolism, Lymphocytes drug effects, Lymphocytes metabolism
- Abstract
Gap junctions (GJs) formed by connexins (Cxs) in T lymphocytes have been reported to have important roles in the T lymphocyte‑driven inflammatory response and hypertension‑mediated inflammation. Estrogen has a protective effect on cardiovascular diseases, including hypertension and it attenuates excessive inflammatory responses in certain autoimmune diseases. However, the mechanisms involved in regulating the pro‑inflammatory response are complex and poorly understood. The current study investigated whether β‑estradiol suppresses hypertension and pro‑inflammatory stimuli‑mediated inflammatory responses by regulating Cxs and Cx‑mediated GJs in peripheral blood lymphocytes. Male, 16‑week‑old spontaneously hypertensive rats (SHR) and Wistar‑Kyoto rats (WKY) rats were randomly divided into the following three groups: WKY rats, vehicle (saline)‑treated SHRs, and β‑estradiol (20 µg/kg/day)‑treated SHRs. β‑estradiol was administered subcutaneously for 5 weeks. Hematoxylin and eosin staining was performed to evaluate target organ injury. Flow cytometry and ELISA were used to measure the populations of T lymphocyte subtypes in the peripheral blood, and expression of Cx40/Cx43 in T cell subtypes, and pro‑inflammation cytokines levels, respectively. ELISA, a dye transfer technique, immunofluorescence and immunoblotting were used to analyze the effect of β‑estradiol on pro‑inflammatory cytokine secretion, Cx‑mediated GJs and the expression of Cxs in concanavalin A (Con A)‑stimulated peripheral blood lymphocytes isolated from WKY rat. β‑estradiol significantly decreased blood pressure and inhibited hypertension‑induced target organ injury in SHRs. Additionally, β‑estradiol treatment significantly improved the immune homeostasis of SHRs, as demonstrated by the decreased percentage of cluster of differentiation (CD)4+/CD8+ T‑cell subset ratio, reduced serum levels of pro‑inflammatory cytokines and increased the percentage of CD4+CD25+ T cells. β‑estradiol also markedly reduced the expression of Cx40/Cx43 in T lymphocytes from SHRs. In vitro, β‑estradiol significantly suppressed the production of pro‑inflammatory cytokines, reduced communication via Cx‑mediated gap junctions and decreased the expression of Cx40/Cx43 in Con A‑stimulated lymphocytes. These results indicate that β‑estradiol attenuates inflammation and end organ damage in hypertension, which may be partially mediated via downregulated expression of Cxs and reduced function of Cx‑mediated GJ.
- Published
- 2019
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13. Prostaglandin E 2 receptors differentially regulate the output of proinflammatory cytokines in myometrial cells from term pregnant women.
- Author
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Zhang YY, Liu WN, You XJ, Gu H, Xu C, and Ni X
- Subjects
- Cells, Cultured, Chromones pharmacology, Female, Humans, Imidazoles pharmacology, Inflammation, Morpholines pharmacology, Phosphatidylinositol 3-Kinases, Pregnancy, Pyridines pharmacology, Cytokines metabolism, Myocytes, Smooth Muscle cytology, Myometrium cytology, Receptors, Prostaglandin E physiology
- Abstract
Prostaglandin (PG) E
2 plays critical roles during pregnancy and parturition. Emerging evidence indicates that human labour is an inflammatory event. We sought to investigate the effect of PGE2 on the output of proinflammatory cytokines in cultured human uterine smooth muscle cells (HUSMCs) from term pregnant women and elucidate the role of subtypes of PGE2 receptors (EP1 , EP2 , EP3 and EP4 ). After drug treatment and/or transfection of each receptor siRNA, the concentrations of inflammatory secreting factors in HUSMCs culture medium were detected by the corresponding ELISA kits. The results showed that, PGE2 increased interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) output, decreased chemokine (c-x-c motif) ligand 8 (CXCL8) output in a dose-dependent manner, but had no effect on IL-1β and chemokine (c-c motif) ligand 2 (CCL-2) secretion of HUSMCs. EP1 /EP3 agonist 17-phenyl-trinor-PGE2 stimulated IL-6 and TNFα whilst suppressing IL-1β and CXCL8 output. The effects of 17-phenyl-trinor-PGE2 on IL-1β and CXCL8 secretion were remained whereas its effect on IL-6 and TNFα output did not occur in the cells with EP3 knockdown. The stimulatory effects of 17-phenyl-trinor-PGE2 on IL-6 and TNFα were remained whereas the inhibitory effects of 17-phenyl-trinor-PGE2 on IL-1β secretion was blocked in the cells with EP1 knockdown. Either of EP2 and EP4 agonists stimulated IL-1β and TNFα output, which was reversed by EP2 and EP4 siRNA, respectively. The inhibitors of phospholipase C (PLC) and protein kinase C (PKC) blocked EP1 /EP3 modulation of TNFα and CXCL8 output. PI3K inhibitor LY294002 and P38 inhibitor SB202190 blocked 17-phenyl-trinor-PGE2 -induced IL-1β and IL-6 output, respectively. The inhibitors of adenylyl cyclase and PKA prevented EP2 and EP4 stimulation of IL-1β and TNFα output, whereas PLC and PKC inhibitors blocked EP2 - and EP4 -induced TNFα output but not IL-1β output. Our data suggest that PGE2 receptors exhibit different effects on the output of various cytokines in myometrium, which can subtly modulate the inflammatory microenvironment in myometrium during pregnancy.- Published
- 2019
14. [The biological functions of cell-to-cell connection over long distance--membrane nanotube].
- Author
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Shen J, Zhang YY, and Xiao H
- Subjects
- Humans, Mitochondria physiology, Cell Communication, Cell Membrane physiology, Gap Junctions physiology, Nanotubes
- Abstract
Cell-to-cell connections provide conduits for signal exchanges, and play important functional roles in physiological and pathological processes of multicellular organisms. Membrane nanotubes are common long-distance connections between cells, not only transfer molecule signals and mitochondria, but also cooperate with gap junction and other cell-to-cell communications to transfer signals. During the last decade, there are many studies about membrane nanotubes, which focus on the similarities and differences between membrane nanotubes and other cell-to-cell communications, as well as their biological functions. In the present review, we summarized the latest findings about the structural diversity, the similarities and differences in signal transmission with other types of cell-to-cell communications, and physiological and pathological roles of membrane nanotubes.
- Published
- 2019
15. [Research advances of autonomic nervous system in the regulation of cardiac inflammation].
- Author
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Feng YN, Xiao H, and Zhang YY
- Subjects
- Humans, alpha7 Nicotinic Acetylcholine Receptor physiology, Autonomic Nervous System physiology, Heart physiopathology, Inflammation physiopathology, Parasympathetic Nervous System physiology
- Abstract
The autonomic nervous system consists of the sympathetic nervous system and the parasympathetic nervous system. These two systems control the heart and work in a reciprocal fashion to modulate myocardial energy metabolism, heart rate as well as blood pressure. Multiple cardiac pathological conditions are accompanied by autonomic imbalance, characterized by sympathetic overactivation and parasympathetic inhibition. Studies have shown that overactive sympathetic nervous system leads to increased cardiac inflammatory reaction. Orchestrated inflammatory response serves to clear dead cardiac tissue and activate reparative process, whereas excessive inflammation may result in pathological cardiac remodeling. Since the discovery of the α7 nicotinic acetylcholine receptor (α7nAChR)-mediated cholinergic anti-inflammatory pathway (CAP), the protective effects of the parasympathetic nervous system in cardiac inflammation have attracted more attention recently. In this review, we summarized the role and underlying mechanisms of the sympathetic and parasympathetic nervous systems in cardiac inflammation, in order to provide new insight into cardiac inflammatory response in cardiovascular diseases.
- Published
- 2019
16. Admission macrophage migration inhibitory factor predicts long-term prognosis in patients with ST-elevation myocardial infarction.
- Author
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Deng XN, Wang XY, Yu HY, Chen SM, Xu XY, Huai W, Liu GH, Ma QB, Zhang YY, Dart AM, Du XJ, and Gao W
- Subjects
- Biomarkers blood, Cause of Death trends, China epidemiology, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prognosis, Retrospective Studies, Risk Factors, ST Elevation Myocardial Infarction mortality, ST Elevation Myocardial Infarction surgery, Survival Rate trends, Time Factors, Intramolecular Oxidoreductases blood, Macrophage Migration-Inhibitory Factors blood, Patient Admission, Percutaneous Coronary Intervention, ST Elevation Myocardial Infarction blood
- Abstract
Aims: We previously showed in patients with ST-segment elevated myocardial infarction (STEMI) that admission levels of macrophage migration inhibitory factor (MIF) predict infarct size. We studied whether admission MIF alone or in combination with other biomarkers is useful for risk assessment of acute and chronic clinical outcomes in STEMI patients., Methods and Results: A total of 658 STEMI patients treated with primary percutaneous coronary intervention (PCI) were consecutively recruited. MIF level was determined at admission and echocardiography performed on day-3 and then 12 months post-MI. Patients were followed for a median period of 64 months. Major endpoints included ST-segment resolution, all-cause mortality, and major adverse cardiovascular events (MACE). High MIF level was associated with larger enzymatic infarct size, incomplete resolution of ST-segment elevation post-PCI, impaired left ventricular ejection fraction (LVEF), and poorer improvement of LVEF (all P < 0.001). After adjustment for classical risk factors standard biomarkers and day-3 LVEF, admission MIF remained independently prognostic for all-cause mortality [hazard ratio (HR) 2.27, 95% confidence interval (CI) 1.43-3.22], and MACE (HR 1.39, 95% CI 1.12-1.71, both P < 0.05). MIF was a significant additive predictor of all-cause mortality with a net reclassification improvement of 0.34 (P = 0.02). Furthermore, patients in high tertile of both admission MIF and day-3 Nt-proBNP had the highest mortality risk relative to other tertile groups (HR 11.28, 95% CI 4.82-26.94; P < 0.001)., Conclusion: STEMI patients with high admission MIF level experienced a poorer recovery of cardiac function and worse long-term adverse outcomes. Combination of Nt-proBNP with MIF further improves prognostic capability.
- Published
- 2018
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17. RNA-binding protein HuR regulates hsa-let-7c expression by its RNA recognition motif.
- Author
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Song Y, Feng W, Shi GM, Chen C, and Zhang YY
- Subjects
- Base Sequence, Computational Biology, Gene Expression Regulation, HEK293 Cells, Humans, AU Rich Elements, ELAV-Like Protein 1 genetics, MicroRNAs genetics, RNA Recognition Motif
- Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that control diverse cellular and developmental events through repression of large sets of target mRNAs. miRNAs expressions were mainly regulated at two levels: transcriptional and post-transcriptional. Transcriptional regulation of miRNA-encoding genes produce specific expression patterns of individual miRNA. However, the mechanism of post-transcriptional regulation of miRNAs remains largely unknown. The present study was aimed to clarify whether HuR, an evolutionary conserved AU-rich binding protein, could regulate miRNAs expressions. By means of a computational screen for AUUUA motifs within pri-miRNAs, we found that the downstream of hsa-let-7c but not hsa-miR-21 was enriched of AUUUA motifs. Then we transfected HuR and mutant HuR lacking RNA recognition motif 3 (RRM3) respectively into HEK293T cells. And HuR protein and miRNAs expressions were detected by Western blot and real-time PCR, respectively. The results showed that the overexpression of HuR promoted mature hsa-let-7c expression but not hsa-miR-21 expression. Furthermore, overexpression of HuR deletion mutant lacking RRM3 did not promote hsa-let-7c expression. These results suggest that RRM3 is crucial for HuR mediating mature hsa-let-7c expression. Collectively, these findings proposed a novel role of HuR in biogenesis of miRNAs, possibly by way of post-transcriptional regulation of miRNAs.
- Published
- 2018
18. Mitochondria are transported along microtubules in membrane nanotubes to rescue distressed cardiomyocytes from apoptosis.
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Shen J, Zhang JH, Xiao H, Wu JM, He KM, Lv ZZ, Li ZJ, Xu M, and Zhang YY
- Subjects
- Animals, Animals, Newborn, Biological Transport, Cell Hypoxia, Kinesins metabolism, Male, Models, Biological, Myocytes, Cardiac metabolism, Myofibroblasts metabolism, Oxygen, Rats, Sprague-Dawley, Apoptosis, Microtubules metabolism, Mitochondria metabolism, Myocytes, Cardiac pathology, Nanotubes chemistry
- Abstract
Membrane nanotubes (MNTs) act as "highways" between cells to facilitate the transfer of multiple signals and play an important role in many diseases. Our previous work reported on the transfer of mitochondria via MNTs between cardiomyocytes (CMs) and cardiac myofibroblasts (MFs); however, the elucidation of the underlying mechanism and pathophysiological significance of this transfer requires additional study. In this study, we determined that the mean movement velocity of mitochondria in MNTs between CMs and MFs was approximately 17.5 ± 2.1 nm/s. Meanwhile, treatment with microtubule polymerisation inhibitors nocodazole or colcemid in cell culture decreased mitochondrial velocity, and knockdown of the microtubule motor protein kinesin family member 5B (KIF5B) led to a similar effect, indicating that mitochondrial movement was dependent on microtubules and the motor protein KIF5B. Furthermore, we showed that hypoxia/reoxygenation-induced CM apoptosis was attenuated by coculture with intact or hypoxia/reoxygenation-treated MFs, which transferred mitochondria to CMs. This rescue was prevented either by separating the cells using Transwell culture or by impairing mitochondrial transfer with nocodazole or colcemid treatment. In conclusion, as a novel means of intercellular communication, MNTs rescue distressed CMs from apoptosis by transporting mitochondria along microtubules via KIF5B.
- Published
- 2018
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19. IL-18 cleavage triggers cardiac inflammation and fibrosis upon β-adrenergic insult.
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Xiao H, Li H, Wang JJ, Zhang JS, Shen J, An XB, Zhang CC, Wu JM, Song Y, Wang XY, Yu HY, Deng XN, Li ZJ, Xu M, Lu ZZ, Du J, Gao W, Zhang AH, Feng Y, and Zhang YY
- Subjects
- Animals, Cytokines metabolism, Fibrosis metabolism, Heart drug effects, Humans, Inflammasomes drug effects, Inflammasomes metabolism, Isoproterenol pharmacology, Male, Mice, Mice, Inbred C57BL, Myocardium immunology, Stress, Physiological drug effects, Stress, Physiological physiology, Adrenergic beta-Agonists pharmacology, Inflammation metabolism, Interleukin-18 metabolism, Myocardium metabolism, Receptors, Adrenergic, beta metabolism
- Abstract
Aims: Rapid over-activation of β-adrenergic receptor (β-AR) upon stress leads to cardiac inflammation, a prevailing factor that underlies heart injury. However, mechanisms by which acute β-AR stimulation induce cardiac inflammation still remain unknown. Here, we set out to identify the crucial role of inflammasome/interleukin (IL)-18 in initiating and maintaining cardiac inflammatory cascades upon β-AR insult., Methods and Results: Male C57BL/6 mice were injected with a single dose of β-AR agonist, isoproterenol (ISO, 5 mg/kg body weight) or saline subcutaneously. Cytokine array profiling demonstrated that chemokines dominated the initial cytokines upregulation specifically within the heart upon β-AR insult, which promoted early macrophage infiltration. Further investigation revealed that the rapid inflammasome-dependent activation of IL-18, but not IL-1β, was the critical up-stream regulator for elevated chemokine expression in the myocardium upon ISO induced β1-AR-ROS signalling. Indeed, a positive correlation was observed between the serum levels of norepinephrine and IL-18 in patients with chest pain. Genetic deletion of IL-18 or the up-stream inflammasome component NLRP3 significantly attenuated ISO-induced chemokine expression and macrophage infiltration. In addition, IL-18 neutralizing antibodies selectively abated ISO-induced chemokines, proinflammatory cytokines and adhesion molecules but not growth factors. Moreover, blocking IL-18 early after ISO treatment effectively attenuated cardiac inflammation and fibrosis., Conclusion: Inflammasome-dependent activation of IL-18 within the myocardium upon acute β-AR over-activation triggers cytokine cascades, macrophage infiltration and pathological cardiac remodelling. Blocking IL-18 at the early stage of β-AR insult can successfully prevent inflammatory responses and cardiac injuries., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2018
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20. [AMP-activated kinase activation inhibits transforming growth factor-β1 production in cardiac fibroblasts via targeting C/EBPβ].
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Xiao H, Piao CS, Chen RF, and Zhang YY
- Subjects
- Aminoimidazole Carboxamide analogs & derivatives, Aminoimidazole Carboxamide pharmacology, Angiotensin II pharmacology, Animals, Binding Sites, Cells, Cultured, Fibrosis, Heart, Mice, Myocardium cytology, Phosphorylation, Ribonucleotides pharmacology, Transfection, AMP-Activated Protein Kinases metabolism, CCAAT-Enhancer-Binding Protein-beta metabolism, Fibroblasts enzymology, Transforming Growth Factor beta1 metabolism
- Abstract
AMP-activated protein kinase (AMPK) activation has been shown to protect against fibrosis. However, the underlying mechanism remains unclear. Here we explored the effect of AMPK activation on transforming growth factor-β1 (TGFβ1) production induced by angiotensin II (AngII) in cardiac fibroblasts and the underlying mechanisms. Adult mouse cardiac fibroblasts were isolated. TGFβ1 and AMPK activity were determined by ELISA and Western blots, respectively. Pretreatment of AMPK activator AICAR inhibited TGFβ1 production induced by AngII in cardiac fibroblasts, which was reversed by AMPK inhibitor compound C. Furthermore, bioinformatics predicted a potential CCAAT/enhancer-binding protein β (C/EBPβ) binding site in the promoter region of the mouse Tgfb1 gene. Luciferase reporter with wild type, but not deleted, C/EBPβ binding sites transfection in mouse embryonic fibroblasts showed increased TGFβ1 transcriptional activity induced by AngII, indicating that C/EBPβ mediates AngII-induced TGFβ1 transcript expression. Pretreatment of AICAR inhibited C/EBPβ expression induced by AngII. In conclusion, AMPK activation inhibited TGFβ1 production induced by AngII in cardiac fibroblasts through targeting C/EBPβ. This finding provides a new mechanism underlying the anti-fibrogenic effects of AMPK activation.
- Published
- 2017
21. Increased circulating β 2 -adrenergic receptor autoantibodies are associated with smoking-related emphysema.
- Author
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Hu JY, Liu BB, Du YP, Zhang Y, Zhang YW, Zhang YY, Xu M, and He B
- Subjects
- Adult, Aged, Animals, Disease Models, Animal, Female, Humans, Male, Middle Aged, Rats, Autoantibodies blood, Emphysema diagnosis, Emphysema pathology, Receptors, Adrenergic immunology, Smoking adverse effects
- Abstract
Smoking is a dominant risk factor for chronic obstructive pulmonary disease (COPD) and emphysema, but not every smoker develops emphysema. Immune responses in smokers vary. Some autoantibodies have been shown to contribute to the development of emphysema in smokers. β
2 -adrenergic receptors (β2 -ARs) are important targets in COPD therapy. β2 -adrenergic receptor autoantibodies (β2 -AAbs), which may directly affect β2 -ARs, were shown to be increased in rats with passive-smoking-induced emphysema in our current preliminary studies. Using cigarette-smoke exposure (CS-exposure) and active-immune (via injections of β2 -AR second extracellular loop peptides) rat models, we found that CS-exposed rats showed higher serum β2 -AAb levels than control rats before alveolar airspaces became enlarged. Active-immune rats showed increased serum β2 -AAb levels, and exhibited alveolar airspace destruction. CS-exposed-active-immune treated rats showed more extensive alveolar airspace destruction than rats undergoing CS-exposure alone. In our current clinical studies, we showed that plasma β2 -AAb levels were positively correlated with the RV/TLC (residual volume/total lung capacity) ratio (r = 0.455, p < 0.001) and RV%pred (residual volume/residual volume predicted percentage, r = 0.454, p < 0.001) in 50 smokers; smokers with higher plasma β2 -AAb levels exhibited worse alveolar airspace destruction. We suggest that increased circulating β2 -AAbs are associated with smoking-related emphysema.- Published
- 2017
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22. Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade.
- Author
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Shang F, Zhang J, Li Z, Zhang J, Yin Y, Wang Y, Marin TL, Gongol B, Xiao H, Zhang YY, Chen Z, Shyy JY, and Lei T
- Subjects
- AMP-Activated Protein Kinases physiology, Animals, Blotting, Western, Cells, Cultured, Endothelium, Vascular cytology, Endothelium, Vascular drug effects, Endothelium, Vascular physiology, Glipizide pharmacology, Humans, MAP Kinase Signaling System physiology, Male, Metoprolol pharmacology, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide metabolism, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases metabolism, Poly(ADP-ribose) Polymerases physiology, Rats, Inbred SHR, Rats, Inbred WKY, Real-Time Polymerase Chain Reaction, Telmisartan, AMP-Activated Protein Kinases drug effects, Benzimidazoles pharmacology, Benzoates pharmacology, Cardiotonic Agents pharmacology, MAP Kinase Signaling System drug effects, Metformin pharmacology, Poly(ADP-ribose) Polymerases drug effects
- Abstract
Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs), diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK) phosphorylation of PARP1 and thus inhibition of PARP1 activity. The results showed that metformin and telmisartan, but not glipizide and metoprolol, activated AMPK, which phosphorylated PARP1 Ser-177 in cultured ECs and the vascular wall of rodent models. Experiments using phosphorylated/de-phosphorylated PARP1 mutants show that AMPK phosphorylation of PARP1 leads to decreased PARP1 activity and attenuated protein poly(ADP-ribosyl)ation (PARylation), but increased endothelial nitric oxide synthase (eNOS) activity and silent mating type information regulation 2 homolog 1 (SIRT1) expression. Taken together, the data presented here suggest biguanides and ARBs have a beneficial effect on the vasculature by the cascade of AMPK phosphorylation of PARP1 to inhibit PARP1 activity and protein PARylation in ECs, thereby mitigating endothelial dysfunction.
- Published
- 2016
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23. Fenoterol inhibits LPS-induced AMPK activation and inflammatory cytokine production through β-arrestin-2 in THP-1 cell line.
- Author
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Wang W, Zhang Y, Xu M, Zhang YY, and He B
- Subjects
- AMP-Activated Protein Kinases antagonists & inhibitors, AMP-Activated Protein Kinases genetics, Adrenergic beta-2 Receptor Agonists pharmacology, Arrestins antagonists & inhibitors, Arrestins genetics, Cell Line, Enzyme Activation drug effects, Gene Knockdown Techniques, Humans, Inflammation Mediators metabolism, Interleukin-1beta biosynthesis, Lipopolysaccharides pharmacology, NF-kappa B metabolism, RNA, Small Interfering genetics, beta-Arrestin 2, beta-Arrestins, AMP-Activated Protein Kinases metabolism, Arrestins metabolism, Cytokines biosynthesis, Fenoterol pharmacology
- Abstract
The AMP-activated protein kinase (AMPK) pathway is involved in regulating inflammation in several cell lines. We reported that fenoterol, a β2-adrenergic receptor (β2-AR) agonist, had anti-inflammatory effects in THP-1 cells, a monocytic cell line. Whether the fenoterol anti-inflammatory effect involves the AMPK pathway is unknown. In this study, we explored the mechanism of β2-AR stimulation with fenoterol in a lipopolysaccharide (LPS)-induced inflammatory cytokine secretion in THP-1 cells. We studied whether fenoterol and β-arrestin-2 or AMPKα1 subunit knockdown could affect LPS-induced AMPK activation, nuclear factor-kappa B (NF-κB) activation and inflammatory cytokine secretion. LPS-induced AMPK activation and interleukin 1β (IL-1β) release were reduced with fenoterol pretreatment of THP-1 cells. SiRNA knockdown of β-arrestin-2 abolished the fenoterol inhibition of LPS-induced AMPK activation and interleukin 1β (IL-1β) release, thus β-arrestin-2 mediated the anti-inflammatory effects of fenoterol on LPS-treated THP-1 cells. In addition, siRNA knockdown of AMPKα1 significantly attenuated the LPS-induced NF-κB activation and IL-1β release, so AMPKα1 was a key signaling molecule involved in LPS-induced inflammatory cytokine production. These results suggested the β2-AR agonist fenoterol inhibited LPS-induced AMPK activation and IL-1β release via β-arrestin-2 in THP-1 cells. The exploration of these mechanisms may help optimize therapeutic agents targeting these pathways in inflammatory diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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24. Serial changes of mean platelet volume in relation to Killip Class in patients with acute myocardial infarction and primary percutaneous coronary intervention.
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Wang XY, Yu HY, Zhang YY, Wang YP, Feng XH, Li ZP, Du XJ, and Gao W
- Subjects
- Acute Disease, Clopidogrel, Echocardiography, Female, Humans, Male, Mean Platelet Volume methods, Middle Aged, Myocardial Infarction surgery, Percutaneous Coronary Intervention mortality, Platelet Aggregation Inhibitors administration & dosage, Prognosis, Ticlopidine administration & dosage, Ticlopidine therapeutic use, Mean Platelet Volume instrumentation, Myocardial Infarction blood, Percutaneous Coronary Intervention methods, Platelet Aggregation Inhibitors therapeutic use, Ticlopidine analogs & derivatives
- Abstract
Introduction: Mean platelet volume (MPV) is related to the reactivity of platelets. Among survivors of acute myocardial infarction (MI), greater MPV is known to be associated with impaired reperfusion and higher mortality. The aims of the study is to investigate the dynamic changes of MPV and the relation between MPV and cardiac function in patients with acute MI and received primary percutaneous coronary intervention (PCI)., Materials and Methods: This retrospective cohort study included patients presented during January 2008 to March 2011 to Peking University Third Hospital with ST-segment elevation MI. All patients received successful PCI. MPV was measured serially, using a Sysmex XE2100 haematology analyser, from admission to day-7 after MI., Results: In 375 patients, MPV was at its highest value (10.2±1.0 fL) and correlated well with platelet distribution width (PDW, r=0.833, p<0.0001) at the admission, and then reduced by 16% within the 24 hours, together with marked weakening of its correlation with PDW. Patients with poorer ventricular function, estimated by high Killip Class (≥2, n=96), had higher MPV values at all-time points. By logistic regression model and after adjusting for related confounders, high MPV remained as an independent predictor of Killip Class ≥2 (OR 1.873, CI 95% 1.373-2.673, p=0.001). Clopidogrel pre-usage resulted in significant MPV reduction on admission., Conclusions: MPV undergoes rapid and dynamic changes during the acute phase of MI, and was higher in patients with high Killip Class, suggesting a predictive value of MPV in ventricular dysfunction and clinical outcome of acute phase of MI., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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25. Identifying patients with chronic hepatitis B at high risk of type 2 diabetes mellitus: a cross-sectional study with pair-matched controls.
- Author
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Shen Y, Zhang J, Cai H, Shao JG, Zhang YY, Liu YM, Qin G, and Qin Y
- Subjects
- Adult, Case-Control Studies, China epidemiology, Cross-Sectional Studies, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 genetics, Educational Status, Fatty Liver, Alcoholic epidemiology, Female, Hepatitis B, Chronic blood, Hepatitis B, Chronic epidemiology, Humans, Hypertriglyceridemia epidemiology, Liver Cirrhosis epidemiology, Male, Middle Aged, Risk Factors, Time Factors, Viral Load, gamma-Glutamyltransferase blood, Diabetes Mellitus, Type 2 etiology, Hepatitis B, Chronic complications
- Abstract
Background: The presence of diabetes mellitus (DM) is associated with increased liver morbidity and mortality risk in patients with chronic hepatitis B (CHB). Aim of this study was to identify factors associated with type 2 diabetes mellitus (T2DM) in CHB patients., Methods: A cross-sectional study with pair-matched controls was conducted in Nantong Third People's Hospital, Nantong University, China. From January 2008 to December 2012, a total of 1783 CHB patients were screened for study subjects, among whom 207 patients with T2DM were enrolled as cases and 207 sex- and age-matched non-DM patients as controls. Demographic, anthropometric, lifestyle, clinical, and laboratory data were obtained from each subject., Results: In the univariate model, thirteen variables showed marked differences between the DM group and non-DM group. Patients with longer duration of CHB (≥15 years) and alcoholic steatosis showed the highest likelihood of T2DM (odds ratio = 5.39 and 4.95; 95% confidence intervals 2.76-10.53 and 1.65-14.91). In the multivariate adjusted analysis, three CHB-related factors, namely high viral load, long duration of illness, and presence of cirrhosis, contributed to substantially increase the likelihood of T2DM, in addition to the other five risk factors including family history of DM, low education level, elevated triglycerides (TG), gamma-glutamyl transferase (GGT) levels, and presence of alcoholic steatosis., Conclusions: Our findings suggest that high viral load, long duration of CHB, presence of cirrhosis, alcoholic steatosis and several other factors may be potential risk factors for development of T2DM in CHB patients. It is of vital importance to monitor glucose in high-risk CHB patients and aggressively intervene on modifiable risk factors.
- Published
- 2015
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26. Pathological hypertrophy reverses β2-adrenergic receptor-induced angiogenesis in mouse heart.
- Author
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Xu Q, Jennings NL, Sim K, Chang L, Gao XM, Kiriazis H, Lee YY, Nguyen MN, Woodcock EA, Zhang YY, El-Osta A, Dart AM, and Du XJ
- Abstract
β-adrenergic activation and angiogenesis are pivotal for myocardial function but the link between both events remains unclear. The aim of this study was to explore the cardiac angiogenesis profile in a mouse model with cardiomyocyte-restricted overexpression of β2-adrenoceptors (β2-TG), and the effect of cardiac pressure overload. β2-TG mice had heightened cardiac angiogenesis, which was essential for maintenance of the hypercontractile phenotype seen in this model. Relative to controls, cardiomyocytes of β2-TGs showed upregulated expression of vascular endothelial growth factor (VEGF), heightened phosphorylation of cAMP-responsive-element-binding protein (CREB), and increased recruitment of phospho-CREB, CREB-binding protein (CBP), and p300 to the VEGF promoter. However, when hearts were subjected to pressure overload by transverse aortic constriction (TAC), angiogenic signaling in β2-TGs was inhibited within 1 week after TAC. β2-TG hearts, but not controls, exposed to pressure overload for 1-2 weeks showed significant increases from baseline in phosphorylation of Ca(2+)/calmodulin-dependent kinase II (CaMKIIδ) and protein expression of p53, reduction in CREB phosphorylation, and reduced abundance of phospho-CREB, p300 and CBP recruited to the CREB-responsive element (CRE) site of VEGF promoter. These changes were associated with reduction in both VEGF expression and capillary density. While non-TG mice with TAC developed compensatory hypertrophy, (2-TGs exhibited exaggerated hypertrophic growth at week-1 post-TAC, followed by LV dilatation and reduced fractional shortening measured by serial echocardiography. In conclusion, angiogenesis was enhanced by the cardiomyocyte (2AR/CREB/VEGF signaling pathway. Pressure overload rapidly inhibited this signaling, likely as a consequence of activated CaMKII and p53, leading to impaired angiogenesis and functional decompensation., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)
- Published
- 2015
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27. Mechanical characterization of cervical squamous carcinoma cells by atomic force microscopy at nanoscale.
- Author
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Ding YX, Cheng Y, Sun QM, Zhang YY, You K, Guo YL, Han D, and Geng L
- Subjects
- Adult, Aged, Biomechanical Phenomena, Carcinoma, Squamous Cell surgery, Case-Control Studies, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Epithelial Cells chemistry, Epithelial Cells metabolism, Epithelial Cells pathology, Female, Humans, Microscopy, Atomic Force instrumentation, Microscopy, Electron, Scanning, Microvilli pathology, Middle Aged, Surface Properties, Uterine Cervical Neoplasms surgery, Carcinoma, Squamous Cell pathology, Microscopy, Atomic Force methods, Uterine Cervical Neoplasms pathology, Uterine Cervicitis pathology
- Abstract
To investigate the nanoscale mechanical properties of exfoliated cervical epithelial cells from patients to further reveal the pathogenesis of cervical cancer and help early diagnose. Exfoliated cells were collected from nine patients with chronic cervicitis or CIN1(control group), 30 patients with CIN2-3 (CIN 2-3 group), and 13 patients with cervical cancer (cervical cancer group). Stiffness of the cells was determined by atomic force microscope (AFM). Expression of P16INK4A was studied by immunocytochemistry. Environmental scanning electron microscopy was performed to observe the surface microtopography of the exfoliated cells. Young's modulus was measured for cells exfoliated from control and patients with CIN 2-3 and cervical cancer by AFM. The results showed that with increasing cervical lesions, the Young's modulus of the exfoliated cervical cells increased (P < 0.05). The modulus of the exfoliated cells was significantly decreased in the three patients 1 year after the surgery compared with the value before the surgery. Expression of P16INK4A in the exfoliated cells had not been statistically significant. Squamous cells from cervical cancer group had dense and disordered microvilli without clear microridges compare to other groups. The Young's modulus is increased from the control group, to CIN2-3 and cervical cancer groups, suggesting that the stiffness of cervical epithelial cells increases gradually with increasing cervical lesions. The changes in the mechanical properties of the exfoliated cells occur earlier than the changes in cell morphology. Therefore, analysis of mechanical properties of the exfoliated cells may be used to aid early diagnosis of the cancer.
- Published
- 2015
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28. [Roles of proinflammatory cytokines in cardiac remodeling induced by sympathetic nervous/catecholamine].
- Author
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Li H and Zhang YY
- Subjects
- Heart Failure, Humans, Atrial Remodeling, Catecholamines blood, Cytokines, Heart physiopathology, Sympathetic Nervous System, Ventricular Remodeling
- Abstract
Sympathetic nervous system is excessively activated under strong stress, which leads to a significant rise of plasma catecholamine concentration, then activates the 13-adrenoceptors ( 13-ARs) in the heart and mediates the development of cardiac remodeling and heart failure. Meanwhile, chronic 13-ARs activation has been proved to be involved in cardiac sterile inflammation by mediating the synthesis and secretion of cytokines, which subsequently mediates cardiac fibrosis and dysfunction. This review summarizes a number of important proinflammatory cytokines involved in the process of cardiac pathological remodeling under chronic adrenergic stimulation and the application of neutralizing antibodies on specifically targeting cytokines in the treatment of cardiovascular diseases.
- Published
- 2014
29. Artificial liver support system improves short- and long-term outcomes of patients with HBV-associated acute-on-chronic liver failure: a single-center experience.
- Author
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Qin G, Shao JG, Wang B, Shen Y, Zheng J, Liu XJ, Zhang YY, Liu YM, Qin Y, and Wang LJ
- Subjects
- Acute-On-Chronic Liver Failure etiology, Acute-On-Chronic Liver Failure mortality, Adult, China epidemiology, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prognosis, Survival Rate trends, Time Factors, Treatment Outcome, Acute-On-Chronic Liver Failure therapy, Hepatitis B complications, Liver, Artificial
- Abstract
For patients with acute-on-chronic liver failure (ACLF), artificial liver support system (ALSS) may help prolong lifespan and function as a bridge to liver transplantation (LT), but data on its long-term benefit are lacking. We conducted this prospective, controlled study to determine the efficacy of ALSS and the predictors of mortality in patients with hepatitis B virus (HBV)-associated ACLF.From January 2003 to December 2007, a total of 234 patients with HBV-associated ACLF not eligible for LT were enrolled in our study. They were allocated to receive either plasma exchange centered ALSS plus standard medical therapy (SMT) (ALSS group, n=104) or SMT alone (control group, n=130). All the patients were followed-up for at least 5 years, or until death.At 90 days, the survival rate of ALSS group was higher than that of the control group (62/104 [60%] vs 61/130 [47%], respectively; P<0.05). Median survival was 879 days in the ALSS group (43% survival at 5 years) and 649 days in the control group (31% survival at 5 years, log-rank P<0.05). ALSS was found to be associated with favorable outcome of these patients by both univariate and multivariate analysis. Multivariate Cox regression analysis also revealed that lower serum sodium levels, higher grades of encephalopathy, presence of cirrhosis, hepatorenal syndrome, and higher model for end-stage liver disease scores were independent predictors for both 90-day and 5-year mortality due to ACLF.Our findings suggest that ALSS is safe and may improve the short- and long-term prognosis of patients with HBV-associated ACLF.
- Published
- 2014
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30. [Advanced research in the pathogenesis of stress cardiomyopathy].
- Author
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Wang JJ, Xiao H, and Zhang YY
- Subjects
- Humans, Stress, Physiological, Takotsubo Cardiomyopathy
- Published
- 2014
31. Diverse regulation of cardiac expression of relaxin receptor by α1- and β1-adrenoceptors.
- Author
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Moore XL, Su Y, Fan Y, Zhang YY, Woodcock EA, Dart AM, and Du XJ
- Subjects
- Adrenergic alpha-Agonists pharmacology, Adrenergic alpha-Antagonists pharmacology, Adrenergic beta-Agonists pharmacology, Adrenergic beta-Antagonists pharmacology, Animals, Female, Heart Ventricles drug effects, Heart Ventricles metabolism, Male, Mice, Mice, Transgenic, Myocytes, Cardiac metabolism, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Receptors, Adrenergic, alpha-1 drug effects, Receptors, Adrenergic, beta-1 drug effects, Receptors, G-Protein-Coupled genetics, Receptors, Peptide genetics, Up-Regulation drug effects, Myocytes, Cardiac drug effects, Receptors, Adrenergic, alpha-1 metabolism, Receptors, Adrenergic, beta-1 metabolism, Receptors, G-Protein-Coupled drug effects, Receptors, Peptide drug effects
- Abstract
Purpose: Relaxin, a new drug for heart failure therapy, exerts its cardiac actions through relaxin family peptide receptor 1 (RXFP1). Factors regulating RXFP1 expression remain unknown. We have investigated effects of activation of adrenoceptors (AR), an important modulator in the development and prognosis of heart failure, on expression of RXFP1 in rat cardiomyocytes and mouse left ventricles (LV)., Methods: Expression of RXFP1 at mRNA (real-time PCR) and protein levels (immunoblotting) was measured in cardiomyocytes treated with α- and β-AR agonists or antagonists. RXFP1 expression was also determined in the LV of transgenic mouse strains with cardiac-restricted overexpression of α1A-, α1B- or β2-AR. Specific inhibitors were used to explore signal pathways involved in α1-AR mediated regulation of RXFP1 in cardiomyocytes., Results: In cultured cardiomyocytes, α1-AR stimulation resulted in 2-3 fold increase in RXFP1 mRNA (P < 0.001), which was blocked by specific inhibitors for protein kinase C (PKC) or mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK). Activation of β1-, but not β2-AR, significantly inhibited RXFP1 expression (P < 0.001). Relative to respective wild-type controls, RXFP1 mRNA levels in the LV of mice overexpressing α1A- or α1B-AR were increased by 3- or 10-fold, respectively, but unchanged in β2-AR transgenic hearts. Upregulation by α1-AR stimulation RXFP1 expression was confirmed at protein levels both in vitro and in vivo., Conclusions: Expression of RXFP1 was up-regulated by α1-AR but suppressed by β-AR, mainly β1-AR subtype, in cardiomyocytes. Future studies are warranted to characterize the functional significance of such regulation, especially in the setting of heart failure.
- Published
- 2014
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32. Activation of α1B-adrenoceptors contributes to intermittent hypobaric hypoxia-improved postischemic myocardial performance via inhibiting MMP-2 activation.
- Author
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Gao L, Chen L, Lu ZZ, Gao H, Wu L, Chen YX, Zhang CM, Jiang YK, Jing Q, Zhang YY, and Yang HT
- Subjects
- Actinin metabolism, Adrenergic alpha-1 Receptor Antagonists pharmacology, Animals, Doxycycline pharmacology, Male, Prazosin pharmacology, Protein Kinase C-epsilon metabolism, Rats, Rats, Sprague-Dawley, Signal Transduction drug effects, Tissue Inhibitor of Metalloproteinases metabolism, Tissue Inhibitor of Metalloproteinase-4, Hypoxia metabolism, Matrix Metalloproteinase 2 metabolism, Myocardial Ischemia metabolism, Myocardium metabolism, Receptors, Adrenergic, alpha-1 metabolism, Reperfusion Injury metabolism
- Abstract
Inhibition of matrix metalloproteinases-2 (MMP-2) activation renders cardioprotection from ischemia/reperfusion (I/R) injury; however, the signaling pathways involved have not been fully understood. Intermittent hypobaric hypoxia (IHH) has been shown to enhance myocardial tolerance to I/R injury via triggering intrinsic adaptive responses. Here we investigated whether IHH protects the heart against I/R injury via the regulation of MMP-2 and how the MMP-2 is regulated. IHH (Po2 = 84 mmHg, 4-h/day, 4 wk) improved postischemic myocardial contractile performance, lactate dehydrogenase (LDH) release, and infarct size in isolated perfused rat hearts. Moreover, IHH reversed I/R-induced MMP-2 activation and release, disorders in the levels of MMP-2 regulators, peroxynitrite (ONOO(-)) and tissue inhibitor of metalloproteinase-4 (TIMP-4), and loss of the MMP-2 targets α-actinin and troponin I. This protection was mimicked, but not augmented, by a MMP inhibitor doxycycline and lost by the α1-adrenoceptor (AR) antagonist prazosin. Furthermore, IHH increased myocardial α1A-AR and α1B-AR density but not α1D-AR after I/R. Concomitantly, IHH further enhanced the translocation of PKC epsilon (PKCε) and decreased the release of mitochondrial cytochrome c due to I/R via the activation of α1B-AR but not α1A-AR or α1D-AR. IHH-conferred cardioprotection in the postischemic contractile function, LDH release, MMP-2 activation, and nitrotyrosine as well as TIMP-4 contents were mimicked but not additive by α1-AR stimulation with phenylephrine and were abolished by an α1B-AR antagonist chloroethylclonidine and a PKCε inhibitor PKCε V1-2. These findings demonstrate that IHH exerts cardioprotection through attenuating excess ONOO(-) biosynthesis and TIMP-4 loss and sequential MMP-2 activation via the activation of α1B-AR/PKCε pathway., (Copyright © 2014 the American Physiological Society.)
- Published
- 2014
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33. Growth differentiation factor (GDF)-15 blocks norepinephrine-induced myocardial hypertrophy via a novel pathway involving inhibition of epidermal growth factor receptor transactivation.
- Author
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Xu XY, Nie Y, Wang FF, Bai Y, Lv ZZ, Zhang YY, Li ZJ, and Gao W
- Subjects
- Adrenergic alpha-Agonists administration & dosage, Cardiomegaly chemically induced, Cardiomegaly pathology, Female, Humans, Male, Myocardium metabolism, Myocardium pathology, Norepinephrine administration & dosage, Retrospective Studies, Adrenergic alpha-Agonists adverse effects, Cardiomegaly blood, ErbB Receptors metabolism, Growth Differentiation Factor 15 blood, Norepinephrine adverse effects, Transcriptional Activation drug effects, Up-Regulation drug effects
- Abstract
Accumulating evidence suggests that growth differentiation factor 15 (GDF-15) is associated with the severity and prognosis of various cardiovascular diseases. However, the effect of GDF-15 on the regulation of cardiac remodeling is still poorly understood. In this present study, we demonstrate that GDF-15 blocks norepinephrine (NE)-induced myocardial hypertrophy through a novel pathway involving inhibition of EGFR transactivation. Both in vivo and in vitro assay indicate that NE was able to stimulate the synthesis of GDF-15. The up-regulation of GDF-15 feedback inhibits NE-induced myocardial hypertrophy, including quantitation of [(3)H]leucine incorporation, protein/DNA ratio, cell surface area, and ANP mRNA level. Further research shows that GDF-15 could inhibit the phosphorylation of EGF receptor and downstream kinases (AKT and ERK1/2) induced by NE. Clinical research also shows that serum GDF-15 levels in hypertensive patients were significant higher than in healthy volunteers and were positively correlated with the thickness of the posterior wall of the left ventricle, interventricular septum, and left ventricular mass, as well as the serum level of norepinephrine. In conclusion, NE induces myocardial hypertrophy and up-regulates GDF-15, and this up-regulation of GDF-15 negatively regulates NE-induced myocardial hypertrophy by inhibiting EGF receptor transactivation following NE stimulation.
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- 2014
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34. The ameliorating effects of long-term electroacupuncture on cardiovascular remodeling in spontaneously hypertensive rats.
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Huo ZJ, Li Q, Tian GH, Zhou CM, Wei XH, Pan CS, Yang L, Bai Y, Zhang YY, He K, Wang CS, Li ZG, and Han JY
- Subjects
- Acupuncture Points, Angiotensin II blood, Angiotensin II metabolism, Animals, Aorta metabolism, Collagen metabolism, Endothelin-1 blood, Endothelin-1 metabolism, Enzyme-Linked Immunosorbent Assay, Hypertension blood, Male, Myocardium metabolism, Nitric Oxide blood, Nitric Oxide Synthase metabolism, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Rats, Wistar, Receptor, Angiotensin, Type 1 blood, Receptor, Angiotensin, Type 1 metabolism, Aorta pathology, Blood Pressure, Cardiomegaly therapy, Electroacupuncture, Hypertension therapy, Myocardium pathology, Vascular Remodeling
- Abstract
Background: The purpose of this study was to investigate the inhibitory effects of long-term electroacupuncture at BaiHui (DU20) and ZuSanLi (ST36) on cardiovascular remodeling in spontaneously hypertensive rats (SHR) and underlying mechanisms., Methods: 6-weeks-old SHR or Wistar male rats were randomly, divided into 6 groups: the control group (SHR/Wistar), the non-acupoint electroacupuncture stimulation group (SHR-NAP/Wistar-NAP) and the electroacupuncture stimulation at DU20 and ST36 group (SHR-AP/Wistar-AP), 24 rats in each group. Rats were treated with or without electroacupuncture at DU20 and ST36, once every other day for a period of 8 weeks. The mean arterial pressure (MAP) was measured once every 2 weeks. By the end of the 8th week, the left ventricular structure and function were assessed by echocardiography. The content of angiotensin II (Ang II), endothelin-1 (ET-1) and nitric oxide (NO) in the plasma was determined using enzyme-linked immunosorbent assay. Histological studies on the heart and the ascending aorta were performed. The expression of angiotensin II type 1 receptor (AT1R), endothelin-1 type A receptor (ETAR), eNOS and iNOS in rat myocardium and ascending aorta was investigated by Western blotting., Results: The MAP in SHR increased linearly over the observation period and significantly reduced following electroacupuncture as compared with sham control SHR rats, while no difference in MAP was observed in Wistar rats between electroacupuncture and sham control. The aortic wall thickness, cardiac hypertrophy and increased collagen level in SHR were attenuated by long term electroacupuncture. The content of Ang II, ET-1 in the plasma decreased, but the content of NO increased after electroacupuncture stimulation in SHR. Long term electroacupuncture significantly inhibited the expression of AT1R, ETAR and iNOS, whereas increased eNOS expression, in myocardium and ascending aorta of SHR., Conclusions: The long term electroacupuncture stimulation at DU20 and ST36 relieves the increased MAP and cardiovascular abnormality in both structure and function in SHR, this beneficial action is most likely mediated via modulation of AT1R-AT1R-ET-1-ETAR and NOS/NO pathway.
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- 2014
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35. AMP-activated protein kinase α2 protects against liver injury from metastasized tumors via reduced glucose deprivation-induced oxidative stress.
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Qiu SL, Xiao ZC, Piao CM, Xian YL, Jia LX, Qi YF, Han JH, Zhang YY, and Du J
- Subjects
- AMP-Activated Protein Kinases deficiency, AMP-Activated Protein Kinases genetics, Animals, Cell Line, Tumor, Colonic Neoplasms pathology, Energy Metabolism, Gene Knockout Techniques, Hepatocytes cytology, Hepatocytes metabolism, Hepatocytes pathology, Humans, Liver pathology, Liver Neoplasms pathology, Mice, Mitophagy, Necrosis metabolism, Reactive Oxygen Species metabolism, AMP-Activated Protein Kinases metabolism, Glucose deficiency, Liver injuries, Liver metabolism, Liver Neoplasms metabolism, Liver Neoplasms secondary, Oxidative Stress
- Abstract
It is well known that tumors damage affected tissues; however, the specific mechanism underlying such damage remains elusive. AMP-activated protein kinase (AMPK) senses energetic changes and regulates glucose metabolism. In this study, we examined the mechanisms by which AMPK promotes metabolic adaptation in the tumor-bearing liver using a murine model of colon cancer liver metastasis. Knock-out of AMPK α2 significantly enhanced tumor-induced glucose deprivation in the liver and increased the extent of liver injury and hepatocyte death. Mechanistically, we observed that AMPK α2 deficiency resulted in elevated reactive oxygen species, reduced mitophagy, and increased cell death in response to tumors or glucose deprivation in vitro. These results imply that AMPK α2 is essential for attenuation of liver injury during tumor metastasis via hepatic glucose deprivation and mitophagy-mediated inhibition of reactive oxygen species production. Therefore, AMPK α2 might represent an important therapeutic target for colon cancer metastasis-induced liver injury.
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- 2014
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36. Echocardiographic assessment of β-adrenoceptor stimulation-induced heart failure with reduced heart rate in mice.
- Author
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Li H, Lu ZZ, Chen C, Song Y, Xiao H, and Zhang YY
- Subjects
- Anesthesia, Inhalation, Anesthetics, Inhalation, Animals, Heart Failure pathology, Heart Function Tests, Hemodynamics drug effects, Isoflurane, Male, Mice, Mice, Inbred C57BL, Myocardium pathology, Ventricular Remodeling, Adrenergic beta-Agonists, Echocardiography methods, Heart Failure chemically induced, Heart Failure diagnostic imaging, Heart Rate drug effects, Isoproterenol
- Abstract
1. Chronic injection with the β-adrenoceptor (β-AR) agonist isoproterenol (ISO) has been commonly used as an animal model of β-AR-induced cardiac remodelling and heart failure. This ISO-treated model usually exhibits significantly decreased conscious heart rate (HR). However, the HR in treatment groups is usually adjusted to the same levels by anaesthesia to assess cardiac geometry and function. In the present study, we report a method of echocardiographic assessment that represents the true cardiac geometry and function under conditions of ISO withdrawal. 2. Briefly, C57BL/6 mice were treated with 5 mg/kg per day ISO for 12 weeks. Cardiac geometry and function were assessed by high-resolution echocardiography in vehicle (saline) - and ISO-treated mice that were either conscious or anaesthetized using different concentrations of isoflurane. 3. The cardiac β-AR response was decreased in ISO-treated mice, as evidenced by markedly decreased conscious HR. Vehicle- and ISO-treated mice did not differ in terms of cardiac geometry or function when HR was adjusted to the same level (400 b.p.m.) in both treatment groups, but cardiac geometry and function did differ when a low (1%) rather than high (1.5% or 2%) isoflurane concentration was used to adjust HR. Furthermore, 3 day ISO withdrawal eliminated the difference in conscious HR between the two groups. In addition, the groups differed in cardiac geometry and function regardless of the isoflurane concentration used. 4. In conclusion, using isoflurane to decrease the HR of treated groups to the same level may mask left ventricular dysfunction in ISO-treated mice. Withdrawal of ISO eliminated the difference in basal HR between the ISO-treated and control groups on echocardiography, allowing a more accurate assessment of cardiac pathological and functional changes., (© 2013 Wiley Publishing Asia Pty Ltd.)
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- 2014
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37. Macrophage migration inhibitory factor for the early prediction of infarct size.
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Chan W, White DA, Wang XY, Bai RF, Liu Y, Yu HY, Zhang YY, Fan F, Schneider HG, Duffy SJ, Taylor AJ, Du XJ, Gao W, Gao XM, and Dart AM
- Subjects
- Aged, Animals, Early Diagnosis, Female, Humans, Macrophage Migration-Inhibitory Factors, Male, Mice, Mice, Inbred C57BL, Middle Aged, Predictive Value of Tests, Myocardial Infarction blood, Myocardial Infarction pathology
- Abstract
Background: Early diagnosis and knowledge of infarct size is critical for the management of acute myocardial infarction (MI). We evaluated whether early elevated plasma level of macrophage migration inhibitory factor (MIF) is useful for these purposes in patients with ST-elevation MI (STEMI)., Methods and Results: We first studied MIF level in plasma and the myocardium in mice and determined infarct size. MI for 15 or 60 minutes resulted in 2.5-fold increase over control values in plasma MIF levels while MIF content in the ischemic myocardium reduced by 50% and plasma MIF levels correlated with myocardium-at-risk and infarct size at both time-points (P < 0.01). In patients with STEMI, we obtained admission plasma samples and measured MIF, conventional troponins (TnI, TnT), high sensitive TnI (hsTnI), creatine kinase (CK), CK-MB, and myoglobin. Infarct size was assessed by cardiac magnetic resonance (CMR) imaging. Patients with chronic stable angina and healthy volunteers were studied as controls. Of 374 STEMI patients, 68% had elevated admission MIF levels above the highest value in healthy controls (> 41.6 ng/mL), a proportion similar to hsTnI (75%) and TnI (50%), but greater than other biomarkers studied (20% to 31%, all P < 0.05 versus MIF). Only admission MIF levels correlated with CMR-derived infarct size, ventricular volumes and ejection fraction (n = 42, r = 0.46 to 0.77, all P < 0.01) at 3 day and 3 months post-MI., Conclusion: Plasma MIF levels are elevated in a high proportion of STEMI patients at the first obtainable sample and these levels are predictive of final infarct size and the extent of cardiac remodeling.
- Published
- 2013
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38. Ultrastructural uncoupling between T-tubules and sarcoplasmic reticulum in human heart failure.
- Author
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Zhang HB, Li RC, Xu M, Xu SM, Lai YS, Wu HD, Xie XJ, Gao W, Ye H, Zhang YY, Meng X, and Wang SQ
- Subjects
- Aged, Calcium Signaling, Cardiomyopathy, Dilated pathology, Excitation Contraction Coupling, Humans, Membrane Proteins physiology, MicroRNAs physiology, Middle Aged, Myocardial Ischemia pathology, Heart Failure pathology, Myocytes, Cardiac ultrastructure, Sarcoplasmic Reticulum ultrastructure
- Abstract
Aims: Chronic heart failure is a complex clinical syndrome with impaired myocardial contractility. In failing cardiomyocytes, decreased signalling efficiency between the L-type Ca(2+) channels (LCCs) in the plasma membrane (including transverse tubules, TTs) and the ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) underlies the defective excitation-contraction (E-C) coupling. It is therefore intriguing to know how the LCC-RyR signalling apparatus is remodelled in human heart failure., Methods and Results: Stereological analysis of transmission electron microscopic images showed that the volume densities and the surface areas of TTs and junctional SRs were both decreased in heart failure specimens of dilated cardiomyopathy (DCM) and ischaemic cardiomyopathy (ICM). The TT-SR junctions were reduced by ~60%, with the remaining displaced from the Z-line areas. Moreover, the spatial span of individual TT-SR junctions was reduced by ~17% in both DCM and ICM tissues. In accordance with these remodelling, junctophilin-2 (JP2), a structural protein anchoring SRs to TTs, was down-regulated, and miR-24, a microRNA that suppresses JP2 expression, was up-regulated in both heart failure tissues., Conclusion: Human heart failure of distinct causes shared similar physical uncoupling between TTs and SRs, which appeared attributable to the reduced expression of JP2 and increased expression of miR-24. Therapeutic strategy against JP2 down-regulation would be expected to protect patients from cardiac E-C uncoupling.
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- 2013
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39. Revealing binding interaction between seven drugs and immobilized β2-adrenoceptor by high-performance affinity chromatography using frontal analysis.
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Zhao XF, Huang JJ, Li Q, Wei LS, Zheng JB, Zheng XH, Li ZJ, and Zhang YY
- Subjects
- Chromatography, Affinity, Immobilized Proteins, Ligands, Radioligand Assay, Receptors, Adrenergic, beta-2 chemistry
- Abstract
The development of new approaches to study the affinity between ligands and G-protein-coupled receptors proves to be of growing interest for pharmacologists, chemists, and biologists. The aim of this work was to determine the binding of seven drugs to β2-adrenoceptors by frontal analysis using immobilized receptor stationary phase. The dissociation constants (Kd ) were determined to be (3.16 ± 0.09) × 10(-4) M for salbutamol, (4.29 ± 0.12) × 10(-4) M for terbutaline, (6.19 ± 0.16) × 10(-4) M for methoxyphenamine, (2.11 ± 0.07) × 10(-4) M for tulobuterol, (1.82 ± 0.11) × 10(-4) M for fenoterol, (9.75 ± 0.24) × 10(-6) M formoterol, and (9.84 ± 0.26) × 10(-5) M for clenbuterol. These results showed a good correlation with the data determined by radioligand binding assay. Further investigations revealed that the dissociation constant mainly attributed to the number of hydrogen bonds in the structures of ligands. This study indicates that affinity chromatography using immobilized receptor stationary phase can be used for the direct determination of drug-receptor binding interactions and has the potential to become a reliable alternative for quantitative studies of ligand-receptor interactions., (Copyright © 2013 John Wiley & Sons, Ltd.)
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- 2013
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40. In vivo suppression of microRNA-24 prevents the transition toward decompensated hypertrophy in aortic-constricted mice.
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Li RC, Tao J, Guo YB, Wu HD, Liu RF, Bai Y, Lv ZZ, Luo GZ, Li LL, Wang M, Yang HQ, Gao W, Han QD, Zhang YY, Wang XJ, Xu M, and Wang SQ
- Subjects
- Animals, Aortic Stenosis, Subvalvular complications, Calcium Channels, L-Type physiology, Calcium Signaling physiology, Disease Progression, Drug Evaluation, Preclinical, Gene Expression Regulation, Heart Failure etiology, Heart Failure metabolism, Hypertrophy, Left Ventricular complications, Hypertrophy, Left Ventricular physiopathology, Male, Membrane Proteins antagonists & inhibitors, Mice, Mice, Inbred C57BL, MicroRNAs genetics, MicroRNAs physiology, Models, Cardiovascular, Myocardial Contraction drug effects, Myocytes, Cardiac metabolism, Myocytes, Cardiac ultrastructure, Oligonucleotides, Antisense pharmacology, Ryanodine Receptor Calcium Release Channel physiology, Sarcoplasmic Reticulum drug effects, Sarcoplasmic Reticulum physiology, Sarcoplasmic Reticulum ultrastructure, Calcium Signaling drug effects, Excitation Contraction Coupling drug effects, Heart Failure prevention & control, Hypertrophy, Left Ventricular drug therapy, MicroRNAs antagonists & inhibitors, Myocytes, Cardiac drug effects, Oligonucleotides, Antisense therapeutic use
- Abstract
Rationale: During the transition from compensated hypertrophy to heart failure, the signaling between L-type Ca(2+) channels in the cell membrane/T-tubules and ryanodine receptors in the sarcoplasmic reticulum becomes defective, partially because of the decreased expression of a T-tubule-sarcoplasmic reticulum anchoring protein, junctophilin-2. MicroRNA (miR)-24, a junctophilin-2 suppressing miR, is upregulated in hypertrophied and failing cardiomyocytes., Objective: To test whether miR-24 suppression can protect the structural and functional integrity of L-type Ca(2+) channel-ryanodine receptor signaling in hypertrophied cardiomyocytes., Methods and Results: In vivo silencing of miR-24 by a specific antagomir in an aorta-constricted mouse model effectively prevented the degradation of heart contraction, but not ventricular hypertrophy. Electrophysiology and confocal imaging studies showed that antagomir treatment prevented the decreases in L-type Ca(2+) channel-ryanodine receptor signaling fidelity/efficiency and whole-cell Ca(2+) transients. Further studies showed that antagomir treatment stabilized junctophilin-2 expression and protected the ultrastructure of T-tubule-sarcoplasmic reticulum junctions from disruption., Conclusions: MiR-24 suppression prevented the transition from compensated hypertrophy to decompensated hypertrophy, providing a potential strategy for early treatment against heart failure.
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- 2013
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41. Profiling of microRNA-mRNA reveals roles of microRNAs in cervical cancer.
- Author
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Ma D, Zhang YY, Guo YL, Li ZJ, and Geng L
- Subjects
- Adult, Computational Biology, Female, Humans, Middle Aged, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, MicroRNAs genetics, RNA, Messenger genetics, Uterine Cervical Neoplasms genetics
- Abstract
Background: Cervical cancer is one of the most common malignant tumors in women. This study was designed to explore the expression profiles of microRNAs (miRNAs) and mRNAs and the gene regulation network in cervical tumorigenesis and to find candidate molecular markers and key tumorigenic genes in cervical cancer., Methods: miRNAs and mRNAs expression microarrays were used to detect the expression of miRNAs and mRNAs in normal and cancer cervical tissues. TargetScan 5.0 database (UK) was used to predict the target genes of the miRNAs, analyze their intersection with differentially expressed mRNAs and negatively correlate the intersection with miRNAs. Bioinformatic approaches were used to analyze functions and pathways of the target genes and establish miRNA-gene network., Results: Twenty-nine miRNAs and 2036 mRNAs were differentially expressed in normal and cervical tumor tissues. Among them, 13 miRNAs and 754 mRNAs were up-regulated in cervical tumor tissues and 16 miRNAs and 1282 RNA were down-regulated. The 327 target genes negatively related to miRNAs in the intersection were involved in functions and signal pathways. Down-regulated miRNAs targeted genes and up-regulated miRNAs targeted genes were involved in 415 and 163 functions, respectively, and in 37 and 17 significant pathways, respectively (P < 0.05, false discovery rate (FDR) < 0.05). We constructed the miRNAs-gene network and found that hsa-miR-15a, hsa-miR-106b and hsa-miR-20b were key nodes in the network., Conclusions: The differentially expressed miRNAs and mRNAs in cervical cancer and related miRNA-gene network have been identified. They play important roles in cervical tumorigenesis and are involved in many important biological functions and signal transduction pathways. These findings lay a foundation for research on the molecular mechanism of miRNAs in the pathogenesis of cervical cancer.
- Published
- 2012
42. Mir-24 regulates junctophilin-2 expression in cardiomyocytes.
- Author
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Xu M, Wu HD, Li RC, Zhang HB, Wang M, Tao J, Feng XH, Guo YB, Li SF, Lai ST, Zhou P, Li LL, Yang HQ, Luo GZ, Bai Y, Xi JJ, Gao W, Han QD, Zhang YY, Wang XJ, Meng X, and Wang SQ
- Subjects
- Animals, Aortic Valve Stenosis pathology, Calcium metabolism, Cells, Cultured, Computational Biology, Excitation Contraction Coupling physiology, Heart Failure pathology, Membrane Proteins genetics, MicroRNAs genetics, Models, Animal, Myocytes, Cardiac pathology, RNA, Messenger metabolism, Rats, Sarcoplasmic Reticulum physiology, Aortic Valve Stenosis metabolism, Heart Failure metabolism, Membrane Proteins metabolism, MicroRNAs metabolism, Myocytes, Cardiac metabolism, Up-Regulation
- Abstract
Rationale: Failing cardiomyocytes exhibit decreased efficiency of excitation-contraction (E-C) coupling. The downregulation of junctophilin-2 (JP2), a protein anchoring the sarcoplasmic reticulum to T-tubules, has been identified as a major mechanism underlying the defective E-C coupling. However, the regulatory mechanism of JP2 remains unknown., Objective: To determine whether microRNAs regulate JP2 expression., Methods and Results: Bioinformatic analysis predicted 2 potential binding sites of miR-24 in the 3'-untranslated regions of JP2 mRNA. Luciferase assays confirmed that miR-24 suppressed JP2 expression by binding to either of these sites. In the aortic stenosis model, miR-24 was upregulated in failing cardiomyocytes. Adenovirus-directed overexpression of miR-24 in cardiomyocytes decreased JP2 expression and reduced Ca(2+) transient amplitude and E-C coupling gain., Conclusions: MiR-24-mediated suppression of JP2 expression provides a novel molecular mechanism for E-C coupling regulation in heart cells and suggests a new target against heart failure.
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- 2012
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43. Ultrastructural remodelling of Ca(2+) signalling apparatus in failing heart cells.
- Author
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Wu HD, Xu M, Li RC, Guo L, Lai YS, Xu SM, Li SF, Lü QL, Li LL, Zhang HB, Zhang YY, Zhang CM, and Wang SQ
- Subjects
- Action Potentials, Animals, Calcium Channels, L-Type metabolism, Cell Membrane metabolism, Cell Shape, Cells, Cultured, Computer Simulation, Disease Models, Animal, Excitation Contraction Coupling, Gene Knockdown Techniques, Heart Failure genetics, Heart Failure metabolism, Heart Failure physiopathology, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Microscopy, Electron, Transmission, Models, Cardiovascular, Myocytes, Cardiac metabolism, RNA Interference, Rats, Rats, Sprague-Dawley, Ryanodine Receptor Calcium Release Channel metabolism, Sarcoplasmic Reticulum metabolism, Time Factors, Transfection, Calcium Signaling, Cell Membrane ultrastructure, Heart Failure pathology, Myocardial Contraction, Myocytes, Cardiac ultrastructure, Sarcoplasmic Reticulum ultrastructure
- Abstract
Aims: The contraction of a heart cell is controlled by Ca(2+)-induced Ca(2+) release between L-type Ca(2+) channels (LCCs) in the cell membrane/T-tubules (TTs) and ryanodine receptors (RyRs) in the junctional sarcoplasmic reticulum (SR). During heart failure, LCC-RyR signalling becomes defective. The purpose of the present study was to reveal the ultrastructural mechanism underlying the defective LCC-RyR signalling and contractility., Methods and Results: In rat models of heart failure produced by transverse aortic constriction surgery, stereological analysis of transmission electron microscopic images showed that the volume density and the surface area of junctional SRs and those of SR-coupled TTs were both decreased in failing heart cells. The TT-SR junctions were displaced or missing from the Z-line areas. Moreover, the spatial span of individual TT-SR junctions was markedly reduced in failing heart cells. Numerical simulation and junctophilin-2 knockdown experiments demonstrated that the decrease in junction size (and thereby the constitutive LCC and RyR numbers) led to a scattered delay of Ca(2+) release activation., Conclusions: The shrinking and eventual absence of TT-SR junctions are important mechanisms underlying the desynchronized and inhomogeneous Ca(2+) release and the decreased contractile strength in heart failure. Maintaining the nanoscopic integrity of TT-SR junctions thus represents a therapeutic strategy against heart failure and related cardiomyopathies.
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- 2012
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44. Up-regulating relaxin expression by G-quadruplex interactive ligand to achieve antifibrotic action.
- Author
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Gu HP, Lin S, Xu M, Yu HY, Du XJ, Zhang YY, Yuan G, and Gao W
- Subjects
- Animals, Blotting, Western, Cells, Cultured, Chromatin Immunoprecipitation, Circular Dichroism, Enzyme-Linked Immunosorbent Assay, Humans, Male, Microscopy, Confocal, Promoter Regions, Genetic genetics, Rats, Rats, Sprague-Dawley, Relaxin, Berberine pharmacology, Berberine therapeutic use, Endomyocardial Fibrosis metabolism, Endomyocardial Fibrosis therapy, G-Quadruplexes drug effects
- Abstract
Myocardial fibrosis is a key pathological change in a variety of heart diseases contributing to the development of heart failure, arrhythmias, and sudden death. Recent studies have shown that relaxin prevents and reverses cardiac fibrosis. Endogenous expression of relaxin was elevated in the setting of heart disease; the extent of such up-regulation, however, is insufficient to exert compensatory actions, and the mechanism regulating relaxin expression is poorly defined. In the rat relaxin-1 (RLN1, Chr1) gene promoter region we found presence of repeated guanine (G)-rich sequences, which allowed formation and stabilization of G-quadruplexes with the addition of a G-quadruplex interactive ligand berberine. The G-rich sequences and the G-quadruplexes were localized adjacent to the binding motif of signal transducer and activator of transcription (STAT)3, which negatively regulates relaxin expression. Thus, we hypothesized that the formation and stabilization of G-quadruplexes by berberine could influence relaxin expression. We found that berberine-induced formation of G-quadruplexes did increase relaxin gene expression measured at mRNA and protein levels. Formation of G-quadruplexes significantly reduced STAT3 binding to the promoter of relaxin gene. This was associated with consequent increase in the binding of RNA polymerase II and STAT5a to relaxin gene promoter. In cardiac fibroblasts and rats treated with angiotensin II, berberine was found to suppress fibroblast activation, collagen synthesis, and extent of cardiac fibrosis through up-regulating relaxin. The antifibrotic action of berberine in vitro and in vivo was similar to that by exogenous relaxin. Our findings document a novel therapeutic strategy for fibrosis through up-regulating expression of endogenous relaxin.
- Published
- 2012
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45. Effect of polymorphisms in the β2-adrenergic receptor on the susceptibility and pulmonary function of patients with chronic obstructive pulmonary disease: a meta analysis.
- Author
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Niu LM, Liang Y, Xu M, Zhang YY, Zhang Y, and He B
- Subjects
- Case-Control Studies, Cross-Sectional Studies, Forced Expiratory Volume physiology, Genetic Predisposition to Disease genetics, Humans, Respiratory Function Tests, Polymorphism, Genetic genetics, Pulmonary Disease, Chronic Obstructive genetics, Pulmonary Disease, Chronic Obstructive physiopathology, Receptors, Adrenergic, beta-2 genetics
- Abstract
Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous and complex disease of which the pathogenesis remains largely unknown. Many factors could influence COPD development and progression. One of them is the genetic risk factor. A severe hereditary deficiency of alpha-1 antitrypsin is the best genetic proof. Four single nucleotide polymorphisms (SNPs) of beta2-adrenergic receptor (β(2)AR) result in single amino acid substitution. Two loci had been extensively studied and found that they could change the function of β(2)AR. Two SNPs consist of substitutions of glycine for arginine at amino acid position 16, glutamic acid for glutamine at position 27. Many studies proved that polymorphisms at position 16 and 27 altered the lung function of COPD patients or the patient's susceptibility to the development of COPD. However, there was no exclusive conclusion. Therefore, a meta analysis was done to investigate the effect of polymorphisms in the β2-adrenergic receptor (ADRB2) gene on the risk of COPD and lung function., Methods: Comprehensive searches of MEDLINE, Embase, Ovid, HighWire, Cochrane Library, and Chinese databases (CBMdisc, VIP, CNKI, and Wanfang data) from January 1980 to September 2011 were performed, using the keywords: COPD OR chronic obstructive pulmonary disease AND adrenoreceptor OR adrenergic receptor AND polymorphism OR mutation OR variation. Case-control research or cross sectional studies in which diagnosis of COPD met the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines; all the studies reported the ADRB2 genotype at position 16 or 27. Outcomes measured were genotype frequency and forced expiratory volume in the first second (FEV(1)%) in both the case and control., Results: Twelve case-control studies and eight cross-sectional studies were included. Compared to the control (n = 1225), neither Gly/Gly (n = 527) nor Arg/Arg (n = 422) homozygotes at position 16 demonstrated increased susceptibility to COPD, with odds ratios (ORs) of 0.95 (95%CI (0.68, 1.31), z = 0.33, P = 0.740) and 0.82 (95%CI (0.52, 1.28), z = 0.88, P = 0.381), respectively. Similar results were obtained for position 27, with ORs of 0.97 (95%CI (0.77, 1.23), z = 0.21, P = 0.833) for Glu/Glu homozygotes (n = 357) and 0.82 (95%CI (0.53, 1.29), z = 0.85, P = 0.393) for Gln/Gln homozygotes (n = 704) (control = 1183). In patients with COPD, Arg/Arg homozygotes (n = 41) had a similar FEV1% compared with Gly/Gly homozygotes (n = 102) (standardized mean difference (SMD) = 0.88, 95%CI (-0.85, 2.62), z = 1.00, P = 0.319). The genotype distribution was different between Caucasian and Asian populations (all P < 0.05 except the genotype Arg/Gly) for both position 16 and 27., Conclusions: Polymorphisms of ADRB2 at positions 16 and 27 did not change the risk of COPD nor affect lung function or disease severity. The genotype distribution for these polymorphisms was different between Caucasian and Asian populations.
- Published
- 2012
46. Inhibition of the STAT3 signaling pathway is involved in the antitumor activity of cepharanthine in SaOS2 cells.
- Author
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Chen Z, Huang C, Yang YL, Ding Y, Ou-Yang HQ, Zhang YY, and Xu M
- Subjects
- Animals, Cell Cycle Checkpoints drug effects, Cell Line, Tumor drug effects, Cyclin D1 genetics, Cyclin D1 metabolism, Humans, Mice, Mice, Nude, Neoplasm Transplantation, Proto-Oncogene Proteins c-myc metabolism, Random Allocation, bcl-X Protein metabolism, Antineoplastic Agents, Phytogenic pharmacology, Benzylisoquinolines pharmacology, STAT3 Transcription Factor metabolism, Signal Transduction drug effects
- Abstract
Aim: To investigate the molecular mechanisms underlying the antitumor activity of cepharanthine (CEP), an alkaloid extracted from Stephania cepharantha Hayata., Methods: Human osteosarcoma cell line SaOS2 was used. MTT assay, Hoechst 33342 nuclear staining, flow cytometry, Western blotting and nude mouse xenografts of SaOS2 cells were applied to examine the antitumor activity of CEP in vitro and in vivo. The expression levels of STAT3 and its downstream signaling molecules were measured with Western blotting and immunochemistry analysis. The activity of STAT3 was detected based on the phosphorylation level of STAT3, luciferase gene reporter assay and translocation of STAT3 to the nucleus., Results: Treatment of SaOS2 cells with CEP (2.5-20 μmol/L) inhibited the cell growth in a concentration- and time-dependent manner. CEP (10 μmol/L) caused cell cycle arrest at G(1) phase and induced apoptosis of SaOS2 cells. CEP (10 and 15 μmol/L) significantly decreased the expression of STAT3 in SaOS2 cells. Furthermore, CEP (5 and 10 μmol/L) significantly inhibited the expression of target genes of STAT3, including the anti-apoptotic gene Bcl-xL and the cell cycle regulators c-Myc and cyclin D1. In nude mouse xenografts of SaOS2 cells, CEP (20 mg·kg(-1)·d(-1), ip for 19 d) significantly reduced the volume and weight of the tumor., Conclusion: Our findings suggest that inhibition of STAT3 signaling pathway is involved in the anti-tumor activity of CEP.
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- 2012
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47. Proteome reference map and regulation network of neonatal rat cardiomyocyte.
- Author
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Li ZJ, Liu N, Han QD, and Zhang YY
- Subjects
- Animals, Cells, Cultured, Male, Metabolic Networks and Pathways, Proteome isolation & purification, Rats, Rats, Sprague-Dawley, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization methods, Electrophoresis, Gel, Two-Dimensional methods, Myocytes, Cardiac chemistry, Proteome analysis, Proteomics methods
- Abstract
Aim: To study and establish a proteome reference map and regulation network of neonatal rat cardiomyocyte., Methods: Cultured cardiomyocytes of neonatal rats were used. All proteins expressed in the cardiomyocytes were separated and identified by two-dimensional polyacrylamide gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). Biological networks and pathways of the neonatal rat cardiomyocytes were analyzed using the Ingenuity Pathway Analysis (IPA) program (www.ingenuity.com). A 2-DE database was made accessible on-line by Make2ddb package on a web server., Results: More than 1000 proteins were separated on 2D gels, and 148 proteins were identified. The identified proteins were used for the construction of an extensible markup language-based database. Biological networks and pathways were constructed to analyze the functions associate with cardiomyocyte proteins in the database. The 2-DE database of rat cardiomyocyte proteins can be accessed at http://2d.bjmu.edu.cn., Conclusion: A proteome reference map and regulation network of the neonatal rat cardiomyocytes have been established, which may serve as an international platform for storage, analysis and visualization of cardiomyocyte proteomic data.
- Published
- 2011
- Full Text
- View/download PDF
48. Metformin attenuates pressure overload-induced cardiac hypertrophy via AMPK activation.
- Author
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Fu YN, Xiao H, Ma XW, Jiang SY, Xu M, and Zhang YY
- Subjects
- AMP-Activated Protein Kinases genetics, Animals, Cardiomegaly pathology, Echocardiography, Heart drug effects, Hypoglycemic Agents pharmacology, Metformin pharmacology, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardium pathology, Phosphorylation, AMP-Activated Protein Kinases metabolism, Cardiomegaly drug therapy, Cardiomegaly enzymology, Enzyme Activation drug effects, Hypoglycemic Agents therapeutic use, Metformin therapeutic use
- Abstract
Aim: To identify the role of metformin in cardiac hypertrophy and investigate the possible mechanism underlying this effect., Methods: Wild type and AMPKα2 knockout (AMPKα2⁻/⁻) littermates were subjected to left ventricular pressure overload caused by transverse aortic constriction. After administration of metformin (200 mg·kg⁻¹·d⁻¹) for 6 weeks, the degree of cardiac hypertrophy was evaluated using echocardiography and anatomic and histological methods. The antihypertrophic mechanism of metformin was analyzed using Western blotting., Results: Metformin significantly attenuated cardiac hypertrophy induced by pressure overload in wild type mice, but the antihypertrophic actions of metformin were ablated in AMPKα2⁻/⁻ mice. Furthermore, metformin suppressed the phosphorylation of Akt/protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in response to pressure overload in wild type mice, but not in AMPKα2⁻/⁻ mice., Conclusion: Long-term administration of metformin may attenuate cardiac hypertrophy induced by pressure overload in nondiabetic mice, and this attenuation is highly dependent on AMPK activation. These findings may provide a potential therapy for patients at risk of developing pathological cardiac hypertrophy.
- Published
- 2011
- Full Text
- View/download PDF
49. Transcription factor Ap-1 mediates proangiogenic MIF expression in human endothelial cells exposed to Angiotensin II.
- Author
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Shan ZX, Lin QX, Yang M, Zhang B, Zhu JN, Mai LP, Deng CY, Liu JL, Zhang YY, Lin SG, and Yu XY
- Subjects
- Animals, Base Sequence, Cell Extracts, Cell Nucleus drug effects, Cell Nucleus metabolism, Electrophoretic Mobility Shift Assay, Humans, Macrophage Migration-Inhibitory Factors genetics, Macrophage Migration-Inhibitory Factors pharmacology, Molecular Sequence Data, Rats, Umbilical Veins cytology, Angiogenesis Inducing Agents metabolism, Angiotensin II pharmacology, Endothelial Cells drug effects, Endothelial Cells metabolism, Macrophage Migration-Inhibitory Factors metabolism, Neovascularization, Physiologic drug effects, Transcription Factor AP-1 metabolism
- Abstract
Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with the atherosclerotic process and atherosclerotic plaque stability. MIF was shown to be highly expressed in advanced atherosclerotic lesions. Neutralizing MIF with a blocking antibody induced a regression of established atherosclerotic lesions. In this study, we investigated the mechanism underlying the proangiogenic effect of MIF in human umbilical vein endothelial cells (HUVECs). We showed that MIF induced the expression of angiogenesis-related genes in HUVECs. We also showed that MIF induced tube formation of HUVECs in vitro and in vivo. Angiotensin II (Ang II) could specifically up-regulate MIF expression in HUVECs. Using a luciferase reporter assay, we demonstrated that the AP-1 response element in the 5'-UTR of the MIF gene played a role in Ang II-induced MIF expression. Small hairpin RNA (shRNA) targeting c-Jun, a component of AP-1, and the AP-1 inhibitor CHX both efficiently inhibited MIF expression. The consistent result of electrophoretic mobility shift assay (EMSA) showed that Ang II specifically increased AP-1 activation in HUVECs. Our results suggest that AP-1 mediates Ang II-induced MIF expression which contributes to atherosclerotic plaque destabilization in human endothelial cells., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
50. [SNPs residing in microRNA gene and its target site in the susceptibility of human diseases].
- Author
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Feng W and Zhang YY
- Subjects
- Diabetes Mellitus genetics, Humans, Hypertension genetics, Genetic Predisposition to Disease, MicroRNAs genetics, Neoplasms genetics, Polymorphism, Single Nucleotide
- Published
- 2010
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