腺苷酸活化蛋白激酶调控HMGB1诱导的血管平滑肌细胞表型转化在血管再狭窄中的作用及机制

Restenosis is one of the primary causes which result in poor long-term effects after revascularization with intimal hyperplasia (IH) as its main pathological feature. The key initial step of IH is phenotype switch of vascular smooth muscle cells (VSMCs). High mobility group protein 1(HMGB1) is one of the earliest stimulators that VSMCs are exposed to after vascular injury. Our previous studies showed that HMGB1 induced VSMCs’ phenotype switch, which was inhibited by AMP-activated protein kinase (AMPK). Combined with the related studies, we propose the hypothesis that AMPK inhibits VSMCs’ phenotype switch through inhibiting RAGE (a HMGB1 receptor) endocytosis and ERK1/2/Elk1 signaling; obesity, hypertriglyceridemia and hyperglycemia lead to high risk of restenosis possibly through the exactly same mechanism of suppressing activation of AMPK. This project will launch in-deep study on cell levels, molecular levels and animal levels, provide a new idea for preventing restenosis after vascular reconstruction operation, and provide new theoretical evidence for clinical preventing and treating restenosis via using AMPK agonist and HMGB1 antagonist.

血管再狭窄是血管重建术后远期疗效不佳的主要原因，其病理特征是内膜增生（IH）。血管平滑肌细胞（VSMCs）表型转化是IH的关键始动环节。高迁移率族蛋白1(HMGB1) 是血管损伤后VSMCs最早接触的刺激因子之一。项目组前期研究显示，HMGB1可诱导VSMCs表型转化，腺苷酸活化蛋白激酶（AMPK）抑制HMGB1诱导的VSMCs表型转化。结合相关研究，项目组提出AMPK通过抑制HMGB1受体RAGE内吞和ERK1/2/Elk1激活从而抑制HMGB1诱导的VSMCs表型转化的机制假说，并提出肥胖、高甘油三脂血症和高血糖可能通过抑制AMPK活化这一共同机制导致血管再狭窄高发。项目组拟从细胞、分子及动物三个层次上对上述假说展开深入研究。本项目的完成将为制定防治血管再狭窄的策略提供新的思路，为AMPK激动剂和拮抗HMGB1在临床防治血管再狭窄中的应用提供新的理论依据。