The regulatory roles of H2S in elastin homeostasis in vascular smooth muscle cells

Abstract

The formation and development of elastic fibers in blood vessels are complex and tightly regulated. Enzymatic degradation of elastin by matrix metalloproteinases (MMPs) leads to the degeneration of aortic wall and constitutes the most prominent characteristic of aortic aneurysm. Hydrogen sulfide (H2S) as a new gasotransmitter exhibits a wide variety of vascular protective functions through its anti-inflammatory and anti-oxidative actions. However, the regulatory role of H2S on elastin homeostasis in aortic wall has not yet been explored. Here it was found that an active inflammatory cytokine TNFα could induce MMP2/9 hyperactivity and elastin degradation in cultured vascular smooth muscle cells, which could be reversed by overexpression of cystathionine gamma-lyase (CSE, a major H2S-generating enzyme) or exogenously applied H2S at physiological relevant concentration. In contrast, knockout of CSE enhanced TNFα-induced MMP2/9 hyperactivity and elastin degradation. Neither TNFα nor H2S affected the mRNA or protein expression of MMP9, while H2S reduced MMP2 transcription. In addition, TGFβ1 promoted elastogenesis, but this process was not altered by H2S co-incubation. Furthermore, iron enhanced endogenous generation of H2S, while iron alone or iron and H2S combination had no effect on elastin homeostasis. Taken together, this study suggests that H2S can attenuate dysregulated elastin degradation via decreasing MMP activity. Therefore, CSE/H2S system can be a new therapeutic avenue for the prevention and treatment of elastin dysfunction-related diseases.