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.

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.

• Authors: Dan Zheng, Shiyun Dong, Ting Li, Fan Yang, Xiangjing Yu, Jichao Wu, Xin Zhong, Yajun Zhao, Lina Wang, Changqing Xu, Fanghao Lu, Weihua Zhang
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 36 Issue 3 Pg. 917-29 ( 2015) ISSN: 1421-9778 [Electronic] Germany
• PMID: 26088607 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 S. Karger AG, Basel.

Chemical References

• GYY 4137
• Morpholines
• Organothiophosphorus Compounds
• RNA, Small Interfering
• Reactive Oxygen Species
• Sulfides
• Streptozocin
• NADPH Oxidase 4
• NADPH Oxidases
• Nox4 protein, rat
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9
• sodium bisulfide
• Glucose
• Hydrogen Sulfide

Topics

• Animals
• Animals, Newborn
• Diabetes Mellitus, Experimental (chemically induced, drug therapy, genetics, pathology)
• Fibroblasts (cytology, drug effects, metabolism)
• Gene Expression Regulation
• Glucose (antagonists & inhibitors, pharmacology)
• Hydrogen Sulfide (pharmacology)
• Hyperglycemia (chemically induced, drug therapy, genetics, pathology)
• Male
• Matrix Metalloproteinase 2 (genetics, metabolism)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Morpholines (pharmacology)
• NADPH Oxidase 4
• NADPH Oxidases (antagonists & inhibitors, genetics, metabolism)
• Organothiophosphorus Compounds (pharmacology)
• Primary Cell Culture
• RNA, Small Interfering (genetics, metabolism)
• Rats
• Rats, Wistar
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)
• Signal Transduction
• Streptozocin
• Sulfides (pharmacology)