Hydrogen sulfide‐induced apoptosis of human aorta smooth muscle cells via the activation of mitogen‐activated protein kinases and caspase‐3

Abstract

The endogenous production of hydrogen sulfide (H 2 S) and its physiological functions, including membrane hyperpolarization and smooth muscle cell relaxation, position this gas well in the family of gasotransmitters together with nitric oxide (NO) and carbon monoxide (CO). In this study, we demonstrate that H 2 S at physiologically relevant concentrations induced apoptosis of human aorta smooth muscle cells (HASMCs). Exposure of HASMCs to H 2 S did not induce necrosis as verified with Trypan blue exclusion and LDH release analysis. After inhibiting endogenous H 2 S production, exogenous H 2 S induced much more significant apoptosis, which was not altered by the presence of albumin or glutathione. H 2 S treatment increased the activities of ERK and p38 mitogen‐activated protein kinase (MAPK), but not c‐Jun N‐terminal kinase activity. Suppression of extracellular signal‐regulated kinase (ERK) activity, but not of p38 activity, inhibited the H 2 S‐induced apoptosis of HASMCs. The activation of ERK by H 2 S in HASMCs was accompanied by increased caspase‐3 activity. Inhibition of caspase‐3 by AC‐DEVD‐CHO attenuated the H 2 S‐induced cell apoptosis. Inhibition of ERK by U0126 decreased caspase‐3 activity, whereas AC‐DEVD‐CHO did not alter ERK activity. In conclusion, exogenous H 2 S induces apoptosis of HASMCs, which is significantly affected by the endogenous H 2 S level. Of the three investigated MAPKs, only ERK played an active role in mediating H 2 S‐induced apoptosis of HASMCs by activating caspase‐3. These findings may help reveal novel mechanisms for many diseases linked to H 2 S‐related abnormal cellular proliferation and apoptosis.