HIF‐1α promotes the proliferation and migration of pulmonary arterial smooth muscle cells via activation of Cx43

• Published in: Journal of cellular and molecular medicine Vol. 25; no. 22; pp. 10663 - 10673
• Main Authors: Han, Xiao‐Jian, Zhang, Wei‐Fang, Wang, Qin, Li, Min, Zhang, Chun‐Bo, Yang, Zhang‐Jian, Tan, Ren‐Jie, Gan, Li‐Jun, Zhang, Le‐Ling, Lan, Xue‐Mei, Zhang, Fang‐Lin, Hong, Tao, Jiang, Li‐Ping
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-11-2021; John Wiley and Sons Inc
• Subjects: Adenosine; Animals; Cardiovascular diseases; Cell activation; Cell growth; Cell Proliferation; Cells, Cultured; Chromatin; Connexin 43; Connexin 43 - agonists; Connexin 43 - genetics; Connexin 43 - metabolism; Echinomycin; Experiments; Hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; hypoxia‐induced pulmonary hypertension; Immunohistochemistry; Immunoprecipitation; migration; Models, Biological; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - metabolism; Original; Phosphorylation; proliferation; Promoter Regions, Genetic; Protein Binding; Proteins; Pulmonary arteries; Pulmonary artery; Pulmonary Artery - cytology; Pulmonary Artery - metabolism; pulmonary artery smooth muscle cells; Pulmonary hypertension; Rats; Smooth muscle; Statistical analysis; Veins & arteries; Wound healing; Beijing China; United States > US; China; migration; hypoxia; proliferation; connexin 43; hypoxia-induced pulmonary hypertension; pulmonary artery smooth muscle cells
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.17003

The proliferation of pulmonary artery smooth muscle cells (PASMCs) is an important cause of pulmonary vascular remodelling in hypoxia‐induced pulmonary hypertension (HPH). However, its underlying mechanism has not been well elucidated. Connexin 43 (Cx43) plays crucial roles in vascular smooth muscle cell proliferation in various cardiovascular diseases. Here, the male Sprague‐Dawley (SD) rats were exposed to hypoxia (10% O2) for 21 days to induce rat HPH model. PASMCs were treated with CoCl2 (200 µM) for 24 h to establish the HPH cell model. It was found that hypoxia up‐regulated the expression of Cx43 and phosphorylation of Cx43 at Ser 368 in rat pulmonary arteries and PASMCs, and stimulated the proliferation and migration of PASMCs. HIF‐1α inhibitor echinomycin attenuated the CoCl2‐induced Cx43 expression and phosphorylation of Cx43 at Ser 368 in PASMCs. The interaction between HIF‐1α and Cx43 promotor was also identified using chromatin immunoprecipitation assay. Moreover, Cx43 specific blocker (37,43Gap27) or knockdown of Cx43 efficiently alleviated the proliferation and migration of PASMCs under chemically induced hypoxia. Therefore, the results above suggest that HIF‐1α, as an upstream regulator, promotes the expression of Cx43, and the HIF‐1α/Cx43 axis regulates the proliferation and migration of PASMCs in HPH.