PHB2 Maintains the Contractile Phenotype of VSMCs by Counteracting PKM2 Splicing

作者：Yiting Jia, Chenfeng Mao, Zihan Ma, Jiaqi Huang, Wenqiang Li, Xiaolong Ma, Siting Zhang, Meihong Li, Fang Yu, Yingying Sun, Jingzhou Chen, Juan Feng, Yuan Zhou, Qingbo Xu, Ling Zhao, Yi Fu, Wei Kong · 发表于：Circulation Research · 年份：2022 · DOI：10.1161/circresaha.122.321005 · 被引用次数：104 · 研究领域：RNA Research and Splicing、Congenital heart defects research、Angiogenesis and VEGF in Cancer

Background: Phenotypic transition of vascular smooth muscle cells (VSMCs) accounts for the pathogenesis of a variety of vascular diseases during the early stage. Recent studies indicate the metabolic reprogramming may be involved in VSMC phenotypic transition. However, the definite molecules that link energy metabolism to distinct VSMC phenotype remain elusive. Methods: A carotid artery injury model was used to study postinjury neointima formation as well as VSMC phenotypic transition in vivo. RNA-seq analysis, cell migration assay, collagen gel contraction assay, wire myography assay, immunoblotting, protein interactome analysis, co-immunoprecipitation, and mammalian 2-hybrid assay were performed to clarify the phenotype and elucidate the molecular mechanisms. Results: We collected cell energy-regulating genes by using Gene Ontology annotation and applied RNA-Seq analysis of transforming growth factor-β or platelet-derived growth factor BB stimulated VSMCs. Six candidate genes were overlapped from energy metabolism-related genes and genes reciprocally upregulated by transforming growth factor-β and downregulated by platelet-derived growth factor BB. Among them, prohibitin 2 has been reported to regulate mitochondrial oxidative phosphorylation. Indeed, prohibitin 2-deficient VSMCs lost the contractile phenotype as evidenced by reduced contractile proteins. Consistently, Phb2 SMCKO mice were more susceptible to postinjury VSMC proliferation and neointima formation compared wit...