title: 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: Department of Pediatric Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Yunquan
authors: Y
authors: Li
authors: Department of Physiology, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China.
authors: Guohui
authors: G
authors: Liu
authors: Department of Physiology, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China.
authors: Dianqi
authors: D
authors: Cai
authors: Division II of General Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, P.R. China.
authors: Baoying
authors: B
authors: Pan
authors: Department of Pediatric Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Yuese
authors: Y
authors: Lin
authors: Department of Pediatric Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Xuandi
authors: X
authors: Li
authors: Department of Pediatric Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Shujuan
authors: S
authors: Li
authors: Department of Pediatric Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Ling
authors: L
authors: Zhu
authors: Department of Hypertension and Vascular Diseases, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Xinxue
authors: X
authors: Liao
authors: Department of Pediatric Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Huishen
authors: H
authors: Wang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D003035:Cobalt / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D011464:Epoprostenol / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006861:Hydrogen Peroxide / Q000009:adverse effects; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011651:Pulmonary Artery / Q000166:cytology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013440:Sulfides / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D013440:Sulfides; D003035:Cobalt; D006861:Hydrogen Peroxide; D011464:Epoprostenol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C018021:cobaltous chloride; C025451:sodium bisulfide; D000111:Acetylcysteine; D006862:Hydrogen Sulfide