title: Exogenous Hydrogen Sulfide Attenuates Cardiac Fibrosis Through Reactive Oxygen Species Signal Pathways in Experimental Diabetes Mellitus Models.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zheng
authors.forename: Shiyun
authors.initials: S
authors.lastname: Dong
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Xiangjing
authors.initials: X
authors.lastname: Yu
authors.forename: Jichao
authors.initials: J
authors.lastname: Wu
authors.forename: Xin
authors.initials: X
authors.lastname: Zhong
authors.forename: Yajun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.forename: Changqing
authors.initials: C
authors.lastname: Xu
authors.forename: Fanghao
authors.initials: F
authors.lastname: Lu
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D006943:Hyperglycemia / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013311:Streptozocin; D013440:Sulfides / Q000494:pharmacology
chemical_list: C529376:GYY 4137; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013440:Sulfides; D013311:Streptozocin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C025451:sodium bisulfide; D005947:Glucose; D006862:Hydrogen Sulfide