PKR调控GSDMD介导的内皮细胞超活化促进血管衰老的作用及机制

内皮衰老引起血管平滑肌增殖是导致血管衰老的始动环节。申请人前期研究证实免疫关键靶点PKR在内皮细胞衰老中发挥重要作用，但其促血管衰老的作用及机制尚未阐明。我们预实验发现：老年小鼠血管内膜的PKR活性较年轻小鼠显著升高；老年PKR敲除小鼠的血管衰老程度较同龄野生型小鼠明显降低；敲除PKR可显著抑制GSDMD介导的内皮细胞超活化、免疫炎症因子（IL-1、HMGB1、MCP-1、IP-10）释放及共培养的平滑肌细胞增殖。藉此，我们提出假说：内皮PKR通过促进GSDMD介导的内皮细胞超活化释放免疫炎症因子诱导血管衰老发生。为此，申请人拟进一步在多种血管细胞、基因敲除小鼠以及临床样本层次，通过组织形态学、生理学、分子生物学等手段，深入研究PKR调控GSDMD介导的内皮细胞超活化在促血管衰老过程中的作用及分子机制。本项目的开展将有助于阐明血管衰老的新机制，并为防治老年心血管疾病提供新的理论依据。

Endothelial cell senescence-induced vascular smooth muscle proliferation is the initial factor of vascular aging. Our previous studies confirmed that PKR as a key immune target, plays an important role in endothelial cell senescence, but its role and mechanism in promoting vascular aging have not yet been clarified. Our preliminary experiments found out that compared with young mice, PKR activity is significantly elevated in the endothelium of aged mice. Aged PKR knockout mice exhibits milder vascular aging that compared with aged wild-type mice. Moreover, Knockout of PKR can significantly inhibit the activation of GSDMD-mediated endothelial cell hyperactivation, the release of immune inflammatory (including IL-1, HMGB1, MCP-1 and IP-10) and the proliferation ability of co-cultured smooth muscle cells. Therefore, we hypothesized that endothelial PKR can induce vascular aging by promoting the activation of GSDMD-mediated endothelial cell hyperactivation to releasing aging factors. We purposed to further study the role and molecular mechanism of PKR and GSDMD-mediated endothelial cell hyperactivation in promoting vascular aging by the way of histomorphology, physiology and molecular biology in the levels of cell, mice and clinical samples. These findings will clarify the new mechanism of vascular aging and provide a new method for the prevention and treatment of elderly cardiovascular diseases.