Inhibition of NADPH oxidase 4-related signaling by sodium hydrosulfide attenuates myocardial fibrotic response

Pan, Li-Long; Liu, Xinhua; Shen, Yaqi; Wang, Nuo-Zhou; Xu, Jie; Wu, Dan; Xiong, Qinghui; Deng, Hongkui; Huang, Guoying; Zhu, Yi‐Zhun

doi:10.1016/j.ijcard.2013.06.007

Cited by 72 publications

(74 citation statements)

References 43 publications

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“…For example, exposure of macrophages to LPS resulted in vascular endothelial growth factor expression, which restrained TLR4-NF-κB activation by regulating the PI3-kinase-Akt signaling pathway and SOCS1 expression [41]. In previous study, we have clearly demonstrated that H 2 S, a reducing agent and an antioxidant molecule, is also involved in modulation of intracellular ROS production in a Nox4-dependent manner [20]. An emerging body of evidence suggested that the regulation of CSE expression was subject to redox-dependent mechanisms and was promoted in response to a pro-oxidative cellular environment.…”

Section: Figmentioning

confidence: 94%

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Endogenous Hydrogen Sulfide Ameliorates NOX4 Induced Oxidative Stress in LPS-Stimulated Macrophages and Mice

Wang

Pan

Long

et al. 2018

Cell Physiol Biochem

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Background/Aims: Sepsis is a severe and complicated syndrome that is characterized by dysregulation of host inflammatory responses and organ failure. Cystathionine-γ-lyase (CSE)/ hydrogen sulfide (H₂S) has potential anti-inflammatory activities in a variety of inflammatory diseases. NADPH oxidase 4 (Nox4), a member of the NADPH oxidases, is the major source of reactive oxygen species (ROS) and its expression is increased in sepsis, but its function in CSE-mediated anti-inflammatory activities remains unknown. Methods: Macrophages were either transfected with CSE, Nox4 siRNA or transduced with lentiviral vector encoding CSE or Nox4, and then stimulated with lipopolysaccharide (LPS). The expression of inflammatory mediators and signaling pathway activation were measured by quantitative PCR (qPCR), ELISA, and immunoblotting. LPS-induced shock severity in WT, Nox4 knockdown and CSE knockout (CSE^-/-) mice was assessed. Results: Here we showed that CSE and Nox4 were upregulated in macrophage and mouse in response to LPS. After LPS stimulation, the inflammatory responses were significantly ameliorated by lentiviral Nox4 shRNA knockdown, but were exacerbated by lentiviral overexpressing Nox4. Furthermore, Nox4 mediated inflammation through PI3K/Akt and p-p38 mitogen-activated protein kinase signal pathway. Notably, CSE knockout served to amplify the inflammatory cascade by increasing Nox4-ROS signaling activation in septic mice and macrophage. Similarly, the enhanced production of inflammatory mediators by macrophages was reduced by CSE overexpression. Conclusion: Thus, we demonstrated that CSE/H₂S attenuated LPS-induced sepsis against oxidative stress and inflammation damage probably largely through mediated Nox4 pathway.

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Section: Figmentioning

confidence: 94%

“…Total lysis of the cells or tissues was carried out with RIPA buffers as described before [20]. The protein concentration was determined by protein assay kit (Thermo scientific).…”

Section: Lysate Preparation and Western Blot Analysismentioning

confidence: 99%

Endogenous Hydrogen Sulfide Ameliorates NOX4 Induced Oxidative Stress in LPS-Stimulated Macrophages and Mice

Wang

Pan

Long

et al. 2018

Cell Physiol Biochem

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“…NaHS (100 M) reduces fibroblast proliferation in human atrial fibroblast cells (130). Furthermore, it decreases NADPH oxidase 4, a stimulator of cardiac fibrosis (33), resulting in decreased levels of the profibrotic markers ␣-smooth muscle actin and connective tissue growth factor (114). Oral supplementation of SG1002 (20 mg·kg Ϫ1 ·day Ϫ1 ) reduces fibrosis in a transverse aortic constriction model as assessed by Masson Trichrome and Picrosirius Red staining (78).…”

Section: H 2 S Mitigates Pathological Cardiac Remodeling By Inhibitinmentioning

confidence: 99%

Emerging role of hydrogen sulfide-microRNA crosstalk in cardiovascular diseases

Hackfort

Mishra

2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…CSE is expressed predominantly in the heart and smooth muscle cells in the cardiovascular system [15,16]. Recently, some research groups revealed that treatment with H 2 S ameliorated the process of cardiac remodeling in an injured and failing heart and contributed to cardioprotection [17]. Some datas showed that promoting the activity of CSE could modulate antioxidant defenses and protect against myocardial apoptosis [18].…”

Section: Introductionmentioning

confidence: 99%

Exogenous Hydrogen Sulfide Attenuates Cardiac Fibrosis Through Reactive Oxygen Species Signal Pathways in Experimental Diabetes Mellitus Models

Zheng

Dong

et al. 2015

Cell Physiol Biochem

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Background: Oxidative stress inducing hyperglycemia and high glucose play an important role in the development of cardiac fibrosis associated with diabetic cardiomyopathy. The endogenous gasotransmitter hydrogen sulfide (H₂S) can act in a cytoprotective manner. However, whether H₂S could inhibit the fibrotic process is unclear. The purpose of our study was to examine the role of H₂S in the development and underlying mechanisms behind diabetic cardiomyopathy. Methods: Diabetic cardiomyopathy was induced in rats by injection of streptozotocin (STZ). Cardiac fibrosis and proliferation of rat neonatal cardiac fibroblasts were induced by hyperglycemia and high glucose. We tested the effects of GYY4137 (a slow-releasing H₂S donor), NaHS (an exogenous H₂S donor) and NADPH oxidase 4 (NOX4) siRNA on reactive oxygen species (ROS) production, MMP-2,9, cystathionine-γ-lyase (CSE), NOX4, and extracellular signal-regulated kinase 1/2 (ERK1/2) to reveal the effects of H₂S on the cardiac fibrosis of diabetic cardiomyopathy. Result: In vivo, NaHS treatment inhibited hyperglycemia-induced expression of type I and III collagen, MMP-2 and MMP-9 in diabetic hearts. Rat neonatal cardiac fibroblast migration and cell survival were inhibited by administration of GYY4137. NOX4 expression was increased by hyperglycemia and high glucose, but was reduced in cardiac fibroblasts treated by NaHS and GYY4137. ROS production, ERK1/2 phosphorylation and MMP-2 and 9 expression were decreased in rat neonatal cardiac fibroblasts treated with GYY4137 and NOX4 siRNA. Conclusion: The present study shows that enhanced NOX4 expression results in cardiac fibrosis through ROS-ERK1/2-MAPkinase-dependent mechanisms in diabetic cardiomyopathy. NOX4 could be an important target for H₂S to regulate redox homeostasis in cardiac fibrosis of diabetic cardiomyopathy.

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Inhibition of NADPH oxidase 4-related signaling by sodium hydrosulfide attenuates myocardial fibrotic response

Cited by 72 publications

References 43 publications

Endogenous Hydrogen Sulfide Ameliorates NOX4 Induced Oxidative Stress in LPS-Stimulated Macrophages and Mice

Endogenous Hydrogen Sulfide Ameliorates NOX4 Induced Oxidative Stress in LPS-Stimulated Macrophages and Mice

Emerging role of hydrogen sulfide-microRNA crosstalk in cardiovascular diseases

Exogenous Hydrogen Sulfide Attenuates Cardiac Fibrosis Through Reactive Oxygen Species Signal Pathways in Experimental Diabetes Mellitus Models

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