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Extracellular matrix (ECM) is a non-cellular three-dimensional macromolecular network that not only provides mechanical support but also transduces essential molecular signals in organ functions. ECM is constantly remodeled to control tissue homeostasis, responsible for cell adhesion, cell migration, cell-to-cell communication, and cell differentiation, etc. The dysregulation of ECM components contributes to various diseases, including cardiovascular diseases, fibrosis, cancer, and neurodegenerative diseases, etc. Aberrant ECM remodeling is initiated by various stress, such as oxidative stress, inflammation, ischemia, and mechanical stress, etc. Hydrogen sulfide (H2S) is a gasotransmitter that exhibits a wide variety of cytoprotective and physiological functions through its anti-oxidative and anti-inflammatory actions. Amounting research shows that H2S can attenuate aberrant ECM remodeling. In this review, we discussed the implications and mechanisms of H2S in the regulation of ECM remodeling in cardiovascular diseases, and highlighted the potential of H2S in the prevention and treatment of cardiovascular diseases through attenuating adverse ECM remodeling.

Objective Both estrogen and hydrogen sulfide (H 2 S) are involved in the regulation of atherosclerosis development. We previously reported that male mice with cystathionine gamma-lyase (CSE) gene knockout (CSE-KO) exhibited reduced vascular H 2 S production and increased adhesion molecule expression, which led to early development of atherosclerosis. Estrogen offers significant protection against proliferative cardiovascular diseases in females. The objective of this study is to investigate the impact of estrogen on the anti-atherogenic effect of H 2 S. Methods and results Plasma estrogen (17 β -estradiol) levels were significantly decreased in female CSE-KO mice in comparison with female wild-type (WT) mice. Age-matched female CSE-KO and WT mice were fed with control or atherogenic diet for 12-weeks. Plasma lipid levels, except triglyceride levels, were significantly increased in atherogenic diet-fed WT and CSE-KO mice when compared with control diet-fed groups. However, the extent of lipid change was greater in CSE-KO mice than in WT mice. Atherogenic diet fed female CSE-KO mice, but not WT mice, developed early atherosclerotic lesion. Atherogenic diet induced more atherosclerotic lesion, oxidative stress and intra-cellular adhesion molecule-1 (ICAM-1) expression and nuclear factor kappa B (NF κ B) pathway in female CSE-KO mice when compared with female WT mice. To explore the role of estrogen in early development of atherosclerosis, female WT and CSE-KO mice fed with atherogenic diet were administered subcutaneously with 17 β -estradiol at 80 μg/kg/day for 12 weeks. This treatment suppressed atherogenic factors such as hypercholesterolemia, oxidative stress, ICAM-1 expression and NF κ B pathway in female WT mice, but not in female CSE-KO mice. Conclusions Deficiency of CSE/H 2 S pathway lowered plasma estrogen levels in female mice and nullified the effects of estrogen on hypercholesterolemia, oxidative stress, ICAM-1 expression and atherosclerosis development. Thus, H 2 S is irreplaceable for these vascular effects of estrogen. The impact of this H 2 S dependency of estrogen on atherosclerosis development and the underlying mechanisms remain to be clarified.

Hydrogen sulfide (H2S), a novel member of gasotransmitter family along with nitric oxide and carbon monoxide, exerts a wide range of cellular and molecular actions in our body. Cystathionine gamma-lyase (CSE) is a major H2S-generating enzyme in mammalian. The maintenance of genome integrity is essential for the proper function and survival of all organisms, and DNA damage may result in blockages of transcription and replication, mutagenesis, cellular senescence, and carcinogenesis. In this study, we demonstrated that more DNA damages occur in mouse embryonic fibroblasts (MEFs) from CSE knockout mice in comparison with that from wild-type mice, and H2S at physiologically relevant concentration attenuates DNA damage and cellular senescence in human umbilical vein endothelial cells (HUVECs). Treatment of HUVECs with 10 μM NaHS stimulated poly (ADP-ribosyl) ation (PAR) activation, while knockdown of CSE expression by RNA interference or inhibition of CSE activity by 5 mM DL-propargyglycine attenuated PAR activation. We also observed that H2S stimulates more PAR, XRCC-1 and DNA ligase III complex in HUVECs, while H2S had little effect on the release of apoptosis inducing factor from mitochondria. We further found that PAR levels are significantly higher in liver, kidney and MEFs from wild-type mice when compared with those from CSE knockout mice. H2S induced the interaction of PAR and phosphorylated ERK1/2, and U0126 (an inhibitor of MEK1/2) reversed H2S-induced PAR activation. MEK1, but not MEK2 and PARP-1 were S-sulfhydrated by H2S, following increased ERK1 phosphorylation and PAR activation. These results provide mechanistic insight into how H2S signalling mediates DNA damage and cellular senescence (supported by a grant-in-aid from Heart and Stroke Foundation of Canada to G.Y.).