巴基斯坦卢比
多嘧啶结合蛋白
肺动脉高压
血管平滑肌
厌氧糖酵解
内科学
肺动脉
基因敲除
生物
内分泌学
糖酵解
细胞生物学
医学
丙酮酸激酶
生物化学
新陈代谢
选择性拼接
信使核糖核酸
细胞凋亡
平滑肌
基因
作者
Gui-Feng Lu,Fei Geng,Liping Deng,Da‐Cen Lin,Yan-Zhen Huang,Su‐Mei Lai,Yi-Chen Lin,Long‐Xin Gui,James S.K. Sham,Mo‐Jun Lin
出处
期刊:Hypertension
[Ovid Technologies (Wolters Kluwer)]
日期:2022-11-01
卷期号:79 (11): 2465-2479
被引量:13
标识
DOI:10.1161/hypertensionaha.122.19183
摘要
Pulmonary arterial hypertension maintains rapid cell proliferation and vascular remodeling through metabolic reprogramming. Recent studies suggested that circRNAs play important role in pulmonary vascular remodeling and pulmonary arterial smooth muscle cells proliferation. However, the relationship between circRNA, cell proliferation, and metabolic reprogramming in pulmonary arterial hypertension has not been investigated.RNA-seq and qRT-PCR reveal the differential expression profile of circRNA in pulmonary arteries of pulmonary arterial hypertension rat models. Transfection was used to examine the effects of circSMOC1 on pulmonary artery smooth muscle cells, and the roles of circSMOC1 in vivo were investigated by adenoassociated virus. Mass spectrometry, RNA pull-down, RNA immunoprecipitation, and dual-luciferase reporter assay were performed to investigate the signaling pathway of circSMOC1 regulating the metabolic reprogramming.CircSMOC1 was significantly downregulated in pulmonary arteries of pulmonary arterial hypertension rats. CircSMOC1 knockdown promoted proliferation and migration and enhanced aerobic glycolysis of pulmonary artery smooth muscle cells. CircSMOC1 overexpression in vivo alleviates pulmonary vascular remodeling, right ventricular pressure, and right heart hypertrophy. In the nucleus, circSMOC1 directly binds to PTBP1 (polypyrimidine tract-binding protein), competitively inhibits the specific splicing of PKM (pyruvate kinase M) premRNA, resulting in the upregulation of PKM2 (pyruvate kinase M2), the key enzyme of aerobic glycolysis, to enhance glycolysis. In the cytoplasm, circSMOC1 acted as a miR-329-3p sponge, and its reduction in pulmonary arterial hypertension suppressed PDHB (pyruvate dehydrogenase E1 subunit beta) expression, leading to the impairment of mitochondrial oxidative phosphorylation.circSMOC1 is crucially involved in the metabolic reprogramming of pulmonary artery smooth muscle cells through PTBP1 and miR-329-3p to regulate pulmonary vascular remodeling in pulmonary arterial hypertension.
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