MicroRNA let-7g inhibited hypoxia-induced proliferation of PASMCs via G₀/G₁ cell cycle arrest by targeting c-myc

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• 作者：Wei-Fang Zhang^a ; You-Wen Xiong^b ; Tian-Tian Zhu^c ; Ai-Zhen Xiong^a ; Hui-hui Bao^a ; Xiao-Shu Cheng^a ; ^{xiaoshumenfan@126.com}
• 关键词：HPH ; let-7 ; microRNA ; Cell proliferation ; Vascular remodeling ; Cell cycle
• 刊名：Life Sciences
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：170
• 期：Complete
• 页码：9-15
• 全文大小：1291 K
• 卷排序：170

文摘

Pulmonary hypertension (PH) is a proliferative disorder characterized by enhanced proliferation and suppressed apoptosis of intrapulmonary vascular smooth muscle cells. Recently, network-based bioinformatics have identified let-7 family, a tumor suppressive microRNA, regulate multiple interacting targets relevant to PH. However, the role of let-7 in vascular homeostasis in PH remains unknown. Thus, we wanted to investigate the role of let-7 in hypoxia-induced PASMCs proliferation and the underlying mechanism in hypoxic pulmonary hypertension (HPH).Main methodsThe male Sprague–Dawley (SD) rats were exposed to hypoxia (10% O2) for 21 days to induce HPH. The expression of let-7 was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization. Primary rat PASMCs were exposed to hypoxia (3% O2). MTS and EDU were performed to evaluate PASMCs proliferation. The mRNA and protein expression of c-myc, Bmi-1 and p16 were determined by qRT-PCR and Western blotting, respectively. The functions of let-7g on PASMCs proliferation, c-myc, Bmi-1 and p16 expression were assessed by let-7g mimic and inhibitor transfection.Key findingsAmong let-7 family members, only let-7b and let-7g were significantly down-regulated in remodeled pulmonary artery in HPH rats. Furthermore, only let-7g level was decreased in hypoxic PASMCs. Either hypoxia or let-7g inhibitor stimulated proliferation of PASMCs, let-7g mimic inhibited hypoxia-induced PASMCs proliferation. C-myc was the target of let-7g in PASMCs. Transfect of let-7g mimic inhibited hypoxia-induced c-myc, Bmi-1 up-regulation and p16 down-regulation, which ultimately controls cell cycle progression.SignificanceLoss of inhibition on c-myc-Bmi-1-p16 signaling pathway by let-7g may lead to PASMCs proliferation and vascular remodeling in HPH.