Hydrogen Sulfide Donor GYY4137 Protects against Myocardial Fibrosis.

Xin Tang,Yongfeng Shao,Guoliang Meng,Liping Xie,Zhengrong Huang,Yujiao Xiao,Yu Chen,Rui Wang,Philip K. Moore,Yuqing Zhang,Yong Ji,Albert Ferro,Jinbiao Zhu

doi:10.1155/2015/691070

Abstract

Hydrogen sulfide (H2S) is a gasotransmitter which regulates multiple cardiovascular functions. However, the precise roles of H2S in modulating myocardial fibrosis in vivo and cardiac fibroblast proliferation in vitro remain unclear. We investigated the effect of GYY4137, a slow-releasing H2S donor, on myocardial fibrosis. Spontaneously hypertensive rats (SHR) were administrated with GYY4137 by intraperitoneal injection daily for 4 weeks. GYY4137 decreased systolic blood pressure and inhibited myocardial fibrosis in SHR as evidenced by improved cardiac collagen volume fraction (CVF) in the left ventricle (LV), ratio of perivascular collagen area (PVCA) to lumen area (LA) in perivascular regions, reduced hydroxyproline concentration, collagen I and III mRNA expression, and cross-linked collagen. GYY4137 also inhibited angiotensin II- (Ang II-) induced neonatal rat cardiac fibroblast proliferation, reduced the number of fibroblasts in S phase, decreased collagen I and III mRNA expression and protein synthesis, attenuated oxidative stress, and suppressed α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1) expression as well as Smad2 phosphorylation. These results indicate that GYY4137 improves myocardial fibrosis perhaps by a mechanism involving inhibition of oxidative stress, blockade of the TGF-β1/Smad2 signaling pathway, and decrease in α-SMA expression in cardiac fibroblasts.

Highlights

About two-thirds of cells within the heart consist of nonmyocardial cells, including fibroblasts, smooth muscle cells, and endothelial cells, of which more than 90% are fibroblasts
There was no significant difference of ejection fraction (EF) or fractional shortening (FS) between groups (Figures 1(b)-1(c)), suggesting that GYY4137 does not affect cardiac systolic function in Spontaneously hypertensive rats (SHR) of this age and that the lowering of systolic blood pressure (SBP) by GYY4137 is likely not explained by changes in cardiac function
A few of perivascular collagen fibers were seen in the myocardium of WKY rat, while a number of perivascular collagens accumulated along the myocardial interstitial matrix of SHRs

Summary

Introduction

About two-thirds of cells within the heart consist of nonmyocardial cells, including fibroblasts, smooth muscle cells, and endothelial cells, of which more than 90% are fibroblasts. Using whole cell patch clamping, NaHS has been found to inhibit human atrial fibroblast proliferation induced by transforming growth factor-β1 (TGF-β1) or 20% fetal bovine serum (FBS). H2S attenuates TGF-β1-stimulated Kv4.3 and α-smooth muscle actin (α-SMA) expression, in parallel with its ability to inhibit TGF-β-induced myofibroblast transformation [16]. Huang et al reported that H2S suppressed cardiac fibrosis induced by pressure overload, possibly by inhibiting the activity of intracardiac angiotensin II (Ang II) and by modifying the expression of cx43 [17]. NaHS inhibits Ang II-induced expression of α-SMA, connective tissue growth factor (CTGF), and type I collagen and upregulates the expression of heme oxygenase (HO-1), in cardiac fibroblasts [18]

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