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

Abstract

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

Evidence for a functional vasodilatatory role for hydrogen sulphide in the human cutaneous microvasculature

“…H 2 S upregulates the COX‐2/prostacyclin pathway in isolated human pulmonary artery smooth muscle cells, creating a pro‐vasodilatatory environment (Li et al . ). We found a significant interaction, albeit weaker, between H 2 S and COX byproducts, as indicated by the reduced vascular sensitivity to exogenous H 2 S during concurrent COX inhibition.…”

Exogenous spermine inhibits the proliferation of human pulmonary artery smooth muscle cells caused by chemically-induced hypoxia via the suppression of the ERK1/2- and PI3K/AKT-associated pathways

“…CoCl 2 is a well-known hypoxia mimetic agent that mimics the hypoxic response in many aspects ( 12 ). In the present study, we examined the effects of CoCl 2 at various concentrations and treatment times on the number of viable PASMCs, and we selected the concentration of 50 µ M for 24 h to establish the cell model of hypoxia, as was done in a previous study ( 18 ).…”

Persulfidation of transcription factor FOXO1 at cysteine 457: A novel mechanism by which H2S inhibits vascular smooth muscle cell proliferation

“…Du et al discovered that H 2 S can inhibit VSMC proliferation via the MAPK pathway [7] . Other studies have confirmed that H 2 S suppresses human pulmonary artery smooth muscle cell proliferation by increasing the expression of COX-2/PGI2 [8] . It has also been reported that the VSMCs isolated from CSE-knockout mice exhibit increased proliferation, which involves the cell cycle-related controllers p21 Cip/WAF-1 and cyclin D, compared with those isolated from WT mice [4] .…”