H2S protects against cellular aging via S-sulfhydration of Keap1 and Nrf2 activation in association with oxidative stress.

A therosclerosis is characterized with plaque formation in large and medium-sized blood vessels. The stiffened and narrowed blood vessels limit blood circulation and increase plaque thrombogenicity, which threatens the functionality of vital organs such as the heart and brain. [1][2][3] The development of atherosclerosis is a chronic pathological process. Vascular remodeling and inflammation, endothelial dysfunction, smooth muscle cell (SMC) proliferation and migration, and accumulation of cholesterol-rich lipoproteins in blood vessel walls are early events of atherogenesis, resulting in the recruitment of circulating monocytes, their adhesion to endothelium via adhesion molecules, and their differentiation into macrophages. 4 The subendothelial accumulation of cholesterol-laden macrophages is morphologically recognized as foam cells. In humans, these fatty streaks can progress to more advanced lesions characterized by a lipid-rich necrotic core and a fibrous cap consisting of SMCs and collagen.Lesion rupture can result from the decreased viability of SMCs that is necessary for collagen production and for the structural integrity of the fibrous cap following the release of matrix metalloproteinases from apoptotic macrophages. 4-8 Editorial see p 2472 Clinical Perspective on p 2534Hydrogen sulfide (H 2 S), a member of the gasotransmitter family, plays a number of important physiological roles within the body, including protection against cardiovascular disease.9-11 Cystathionine γ-lyase (CSE) endogenously produces H 2 S in the cardiovascular system, 12,13 and the deficiency of CSE in mice leads to decreased endogenous H 2 S level, age-dependent increase in blood pressure, impaired endothelium-dependent vasorelaxation, and accumulation of homocysteine in the blood.14 Administration of NaHS (a H 2 S donor) protects rat aortic SMCs from the cytotoxicity caused Background-Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H 2 S) in the cardiovascular system. The deficiency of CSE in mice leads to a decreased endogenous H 2 S level, an age-dependent increase in blood pressure, and impaired endothelium-dependent vasorelaxation. To date, there is no direct evidence for a causative role of altered metabolism of endogenous H 2 S in atherosclerosis development. Methods and Results-Six-week-old CSE gene knockout and wild-type mice were fed with either a control chow or atherogenic paigen-type diet for 12 weeks. Plasma lipid profile and homocysteine levels, blood pressure, oxidative stress, atherosclerotic lesion size in the aortic roots, cell proliferation, and adhesion molecule expression were then analyzed. CSE-knockout mice fed with atherogenic diet developed early fatty streak lesions in the aortic root, elevated plasma levels of cholesterol and low-density lipoprotein cholesterol, hyperhomocysteinemia, increased lesional oxidative stress and adhesion molecule expression, and enhanced aortic intimal proliferation. Treatment of CSE-knockout mice with NaHS, but not N-acetylcysteine or ezetimibe, inhibited the acceler...

SMCs-KO display an increased proliferation rate in vitro and in vivo, and these cells are more susceptible to apoptosis induced by exogenous H2S at physiologically relevant concentrations. These cellular effects of H2S are mediated by phosphorylation of ERK1/2 and altered expression of cyclin D1 and p21(Cip/WAF-1).

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Background:The integrated stress response (ISR) maintains cellular homeostasis during aberrant protein folding (ER stress). Results:The ISR enhances glutathione synthesis through up-regulation of cystathionine ␥-lyase via the eIF2␣-ATF4 pathway. Conclusion: Cells undergoing the ISR induce cystathionine ␥-lyase, thereby maintaining cellular homeostasis. Significance: These findings link the cells response to ER stress and redox homeostasis through the ISR.

The efficiency and safety profile of H2S-based therapeutic approaches should be refined, and the mechanisms by which H2S exerts its beneficial effects should be elucidated to develop more specific and potent therapeutic strategies to treat atherosclerosis. Whether the therapeutic effects of H2S in animal studies are transferable to clinical studies merits future investigation.

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Hydrogen sulfide (H2S) can be endogenously generated from cystathionine gamma-lyase (CSE) in cardiovascular system, offering a cardiovascular protection. It is also known that the lower risk of cardiovascular diseases in female is partially attributed to the protective effect of estrogen. The current study explores the interaction of H2S and estrogen on smooth muscle cell (SMC) growth. In the present study, we found that the proliferation of cultured vascular SMCs isolated from wild-type mice (WT-SMCs) was inhibited, but that from CSE gene knockout mice (CSE-KO-SMCs) increased, by estrogen treatments. The expression of estrogen receptor α (ERα), but not ERβ, was significantly decreased in CSE-KO-SMCs compared with that in WT-SMCs. Exogenously applied H2S markedly increased ERα but not ERβ expression. In addition, the inhibition of ER activation and knockdown of ERα expression in WT-SMCs or the overexpression of ERα in CSE-KO-SMCs reversed the respective effects of estrogen on cell proliferation. The expression of cyclin D1 was reduced in WT-SMCs but increased in CSE-KO-SMCs after estrogen treatments, which was reversed by knockdown of ERα in WT-SMCs or overexpression of ERα in CSE-KO-SMCs, respectively. The overexpression of cyclin D1 in WT-SMCs or knockdown of cyclin D1 expression in CSE-KO-SMCs reversed the effects of estrogen on cell proliferation. These results suggest that H2S mediates estrogen-inhibited proliferation of SMCs via selective activation of ERα/cyclin D1 pathways.