Hydrogen sulfide alleviates myocardial collagen remodeling in association with inhibition of TGF-β/Smad signaling pathway in spontaneously hypertensive rats.

Lili Sun,Bin Zhao,Yan Sun,Lujing Sun,Hongfang Jin,Zhenzhen Li,Chaoshu Tang,Jia Liu,Yaqian Huang,Manman Zhao,Junbao Du,Siyao Chen

doi:10.2119/molmed.2013.00096

Abstract

The study was designed to explore the role and possible mechanisms of hydrogen sulfide (H2S) in the regulation of myocardial collagen remodeling in spontaneously hypertensive rats (SHRs). We treated nine-week-old male SHRs and age- and sex-matched Wistar-Kyoto rats (WKYs) with NaHS (90 μmol/kg(-1)·day(-1)) for 9 wks. At 18 wks, plasma H2S, tail arterial pressure, morphology of the heart, myocardial ultrastructure and collagen volume fraction (CVF), myocardial expressions of collagen I and III protein and procollagen I and III mRNA, transforming growth factor-β1 (TGF-β1), TGF-β type I receptor (TβR-I), type II receptor (TβR-II), p-Smad2 and 3, matrix metalloproteinase (MMP)-13 and tissue inhibitors of MMP (TIMP)-1 proteins were determined. TGF-β1-stimulated cultured cardiac fibroblasts (CFs) were used to further study the mechanisms. The results showed that compared with WKYs, SHRs showed a reduced plasma H2S, elevated tail artery pressure and increased myocardial collagen, TGF-β1, TβR-II, p-Smad2 and p-Smad3 expressions. However, NaHS markedly decreased tail artery pressure and inhibited myocardial collagen, TGF-β1, TβR-II, p-Smad2 and p-Smad3 protein expressions, but H2S had no effect on the expressions of MMP-13 and TIMP-1. Hydralazine reduced blood pressure but had no effect on myocardial collagen, MMP-13 and TIMP-1 expressions and TGF-β1/Smad signaling pathway. H2S prevented activation of the TGF-β1/Smad signaling pathway and abnormal collagen synthesis in CFs. In conclusion, the results suggested that H2S could prevent myocardial collagen remodeling in SHR. The mechanism might be associated with inhibition of collagen synthesis via TGF-β1/Smad signaling pathway.

Highlights

Hypertension is one of the most common cardiovascular diseases, endangering human health and life
H2S Content in Rat Plasma Compared with the Wistar–Kyoto rats (WKYs) group, the plasma H2S content was significantly greater in the WKY + NaHS group (P < 0.01) (Figure 1B), but markedly reduced in the spontaneously hypertensive rats (SHRs) group (P < 0.05)
We found that along with the increased tissue inhibitors of MMP (TIMP)-1 expression, the matrix metalloproteinase (MMP)-13 content was markedly decreased in SHRs, suggesting that alterations of the collagen degrading protease system were involved in the development of myocardial collagen remodeling

Summary

Introduction

Hypertension is one of the most common cardiovascular diseases, endangering human health and life. Cardiovascular remodeling is an important pathological change in the development of hypertension and a factor leading to deterioration of the disease [1]. Cardiac fibrosis is a major pathologic feature of hypertensive myocardial remodeling, including interstitial and perivascular fibrosis of intramyocardial coronary arteries. Deposition of collagen type I in the extracellular matrix is the most important factor in myocardial remodeling [3]. Previous studies indicated that cardiac fibrosis was the result of an imbalance between the synthesis and degradation of collagen, characterized by excessive deposition of fibrillar collagen, disproportion of collagen types (increased I/III collagen ratio) and disorganized collagen arrangement [4,5]. The mechanisms responsible for the abnormal metabolisms in hypertension have been unclear

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