HIF2α通过OLR1调控血管平滑肌细胞表型及对动脉粥样硬化进程的影响

动脉粥样硬化（AS）进展为不稳定斑块是急性心血管事件的重要发病基础，血管平滑肌细胞（VSMC）摄取脂质向泡沫化及致炎表型转化是斑块向不稳定发展的早期事件，但调控机制不明。已知低氧贯穿于AS始终，但低氧诱导因子HIF在AS中的贡献尚不明确。课题组前期结果显示，敲除VSMC中HIF2α可显著抑制VSMC泡沫化及致炎表型，并延缓动脉粥样硬化进程，转录组学及生信分析显示脂质摄取关键基因Olr1是HIF2α的重要靶基因，抑制Olr1亦可降低VSMC泡沫化。因而提出假说：HIF2α通过上调靶基因Olr1促进VSMC摄取脂质向泡沫化发展，导致细胞内代谢紊乱及致炎表型，进而加速AS进程。本研究将利用VSMC HIF2α过表达/敲除小鼠及特异性抑制剂，结合转录组学与脂质组学，明确HIF2α/OLR1介导的脂质摄取导致VSMC表型转换并促进AS进程的关键机制，从而为防治AS向不稳定期进展提供潜在靶点。

Vulnerable atherosclerotic plaques are the most important cause for the sudden and unpredictable onset of acute coronary syndrome. The phenotypic switch of vascular smooth muscles (VSMCs) from contractile to foamy and proinflammatory phenotype upon lipid uptake is the early and pivotal event in plaque instability with unknown mechanism. It has been shown that hypoxia exists in all the stages of atherosclerosis. However, the contribution of hypoxia inducible factors (HIF), the key transcription factor mediating cellular adaptive responses to hypoxia, to atherosclerosis remains elusive. Using loss-of-function approach, we showed that HIF2α disruption in VSMCs dramatically attenuated plaque instability in Apoe-/- mice in vivo and suppressed foam cell formation as well as proinflammatory gene expression in oxidized LDL-treated VSMCs in vitro. Transcriptomics and bioinformatic analyses indicated that oxidized low-density lipoprotein receptor 1 (Olr1) is a HIF2α target gene, which was confirmed by ChIP assay. Moreover, OLR1 inhibitor Poly I significantly reduced oxLDL-induced foam cell formation in VSMCs. Therefore, we proposed that HIF2α promotes VSMC-derived foam cell formation and proinflammatory phenotype via its target gene Olr1-mediated lipid uptake and consequent metabolic reprogramming, hence contributing to the increased plaque vulnerability. By using gain- or loss-of-function strategy (VSMC-specific HIF2α-deficient and constitutive HIF2α-activated Apoe-/- mice), chemical inhibitors of HIF2α and OLR1, and combination of transcriptomic and lipidomic approaches, we aimed to determine the effect and molecular mechanisms of HIF2α/OLR1 pathway in VSMC phenotypic switch and features of atherosclerotic plaque instability, thus providing novel potential therapeutic targets for vulnerable atherosclerotic plaques.