H2S inhibition of chemical hypoxia-induced proliferation of HPASMCs is mediated by the upregulation of COX-2/PGI2

The hypoxia-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) is the main cause of pulmonary arterial hypertension (PAH), in which oxidative stress, cyclooxygenase (COX)-2 and hydrogen sulfide (H2S) all play an important role. In the present study, we aimed to examine the effects of H2S on the hypoxia-induced proliferation of human PASMCs (HPASMCs) and to elucidate the underlying mechanisms. The HPASMCs were treated with cobalt chloride (CoCl2), a hypoxia-mimicking agent, to establish a cellular model of hypoxic PAH. Prior to treatment with CoCl2, the cells were pre-conditioned with sodium hydrosulfide (NaHS), a donor of H2S. Cell proliferation, reactive oxygen species (ROS) production, COX-2 expression, prostacyclin (also known as prostaglandin I2 or PGI(2)) secretion and H2S levels were detected in the cells. The exposure of the HPASMCs to CoCl2 markedly increased cell proliferation, accompanied by a decrease in COX-2 expression, PGI(2) secretion and H2S levels; however, the levels of ROS were not altered. Although the exogenous ROS donor, H2O2, triggered similar degrees of proliferation to CoCl2, the ROS scavenger, N-acetyl-L-cysteine (NAC), markedly abolished the H2O2-induced cell proliferation, as opposed to the CoCl2-induced proliferation. The CoCl2-induced proliferation of HPASMCs was suppressed by exogenously applied PGI(2). The addition of H2S (NaHS) attenuated the CoCl2-induced cell proliferation through the increase in the intercellular content of H2S. Importantly, the exposure of the cells to H2S suppressed the CoCl2-induced downregulation in COX-2 expression and PGI(2) secretion from the HPASMCs. In conclusion, the results from the current study suggest that H2S inhibits hypoxia-induced cell proliferation through the upregulation of COX-2/PGI(2), as opposed to ROS.