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

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 enhances hypoxia-induced cell proliferation through the upregulation of COX-2/PGI(2), as opposed to ROS.

• Authors: Yunquan Li, Guohui Liu, Dianqi Cai, Baoying Pan, Yuese Lin, Xuandi Li, Shujuan Li, Ling Zhu, Xinxue Liao, Huishen Wang
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 33 Issue 2 Pg. 359-66 (Feb 2014) ISSN: 1791-244X [Electronic] Greece
• PMID: 24337227 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Reactive Oxygen Species
• Sulfides
• Cobalt
• Hydrogen Peroxide
• Epoprostenol
• Cyclooxygenase 2
• PTGS2 protein, human
• cobaltous chloride
• sodium bisulfide
• Acetylcysteine
• Hydrogen Sulfide

Topics

• Acetylcysteine (pharmacology)
• Cell Hypoxia (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Cobalt (pharmacology)
• Cyclooxygenase 2 (genetics, metabolism)
• Down-Regulation
• Epoprostenol (metabolism)
• Familial Primary Pulmonary Hypertension
• Humans
• Hydrogen Peroxide (adverse effects)
• Hydrogen Sulfide (pharmacology)
• Hypertension, Pulmonary (drug therapy)
• Myocytes, Smooth Muscle (cytology, drug effects, metabolism)
• Oxidative Stress (drug effects)
• Pulmonary Artery (cytology)
• Reactive Oxygen Species (metabolism)
• Sulfides (metabolism)