Myocardin选择性剪接调控内皮间质化在apoA-I抗血管再狭窄中的作用和机制

Despite novel devices used in percutaneous coronary intervention for the treatment of coronary artery diseases, restenosis continues to be a significant impediment to the long-term success of vascular interventions. Restenosis was tightly related to cell proliferation in the subintimal layer, while the origin of smooth muscle-like cells (SMA+) is still in dispute. Endothelial-to-mesenchymal transition (EndMT) is thought to be the novel source of SM-like cells. During EndMT, endothelial cells gain the characteristic marker-SMA of mesenchymal cells. As the core part of high-density lipoprotein (HDL), apolipoprotein A-I inhibits restenosis in an unknown way. Myocardin is known to regulate the expression of SMA. The applicant found that apoA-I can inhibit EndMT and myocardin splicing. RNA-binding protein, Quaking (QKI), is able to influence the mRNA splicing. So it is supposed that apoA-I can upregulate QKI and alter the myocardin splicing, inhibit EndMT, reduce neointimal formation and protect from restenosis. This research focuses on the protective role of apoA-I in restenosis by suppressing EndMT, and trying to prove the mechanism of the anti-restenosis effect of apoA-I. It may provide novel approaches for prevention and treatment of restenosis after vascular intervention.

血管再狭窄严重影响冠心病介入治疗效果，与内膜下细胞增殖密切相关；但新生内膜中表达SMA的平滑肌样细胞来源存在争议。目前发现血管内皮间质化（EndMT）是平滑肌样细胞的重要来源，表现为内皮细胞表达细胞标志SMA。载脂蛋白A-I（apoA-I）作为高密度脂蛋白的重要成分具有抗血管再狭窄的作用，但其是否影响EndMT不清楚。申请人首次发现：apoA-I能在细胞水平抑制内皮间质化，apoA-I干预影响内皮细胞转录调控因子myocardin mRNA剪接异构体比例。鉴于myocardin选择性剪接影响SMA表达，而RNA结合蛋白-Quaking能调控剪接，故假设：apoA-I通过Quaking调控myocardin的选择性剪接，抑制内皮细胞间质化，减少新生内膜形成而抗血管再狭窄。本研究将以EndMT为切入点，以选择性剪接为新机制研究apoA-I抗血管再狭窄的作用，结果将为防治血管再狭窄提供新思路。