Up-regulation of cullin7 promotes proliferation and migration of pulmonary artery smooth muscle cells in hypoxia-induced pulmonary hypertension

• Published in: European journal of pharmacology 2019-12, Vol.864, p.172698-172698, Article 172698
• Main Authors: Liu, Hong, Ge, Xiao-Yue, Huang, Ning, Liu, Ting, Yao, Mao-Zhong, Zhang, Zheng, Qian, Zhao-Xin, Hu, Chang-Ping
• Format: Article
• Language: English
• Subjects: Animals; Cell Movement; Cell Proliferation; Cullin Proteins - genetics; Cullin Proteins - metabolism; Cullin7; Gene Knockdown Techniques; Hypertension, Pulmonary - complications; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - pathology; Hypoxia - complications; Leupeptins - pharmacology; Male; Migration; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; p53; Proliferation; Pulmonary Artery - pathology; Pulmonary artery smooth muscle cells; Pulmonary hypertension; Rats; Rats, Sprague-Dawley; Tumor Suppressor Protein p53 - metabolism; Up-Regulation - drug effects; Vascular Remodeling - drug effects
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2019.172698

It has well been demonstrated that E3 ubiquitin ligase cullin7 plays important roles in cancer cell growth control via down-regulating p53 expression. The noncanonical function or the pathogenic role of p53 has more recently been implicated in pulmonary vascular remodeling. Therefore, whether cullin7 participates in hypoxia-induced pulmonary vascular remodeling deserves to be elucidated. The present study found that hypoxia up-regulated the expression of cullin7 mRNA and protein in pulmonary arteries and pulmonary artery smooth muscle cells, and knockdown of cullin7 inhibited hypoxia-induced proliferation and migration of pulmonary artery smooth muscle cells and reversed hypoxia-induced inhibition of p53 expression. Notably, administration of proteasome inhibitor MG132 significantly inhibited the expression of cullin7 and up-regulated the expression of p53 in pulmonary arteries concomitantly with improvement of hypoxia-induced pulmonary vascular remodeling. Our study demonstrated that hypoxia induced up-regulation of cullin7 expression resulting to the proliferation and migration of pulmonary artery smooth muscle cells via down-regulating p53 expression, which contributed to pulmonary vascular remodeling.