活化型高分子激肽原抑制内皮祖细胞活性在关节炎动脉粥样硬化发展中的作用

类风湿性关节炎(RA)是以关节障碍为主的自身免疫疾病。RA患者高发心血管动脉粥样硬化性疾病是其死亡的主要原因。目前RA血管并发症的发病机制仍不清楚，已成为亟待解决的临床难题。大量研究表明，血浆激肽释放酶-激肽系统(KKS)在关节炎发病中起重要作用。我们研究发现，阻断KKS活化能抑制内皮祖细胞(EPCs)向关节炎症滑膜归巢，并有效控制关节炎发病；KKS活化产物活化型高分子激肽原（HKa）在体外具有抑制EPCs功能的作用，而EPC功能异常与血管内皮障碍密切相关。因此本项目的假说是，KKS活化产物HKa抑制EPCs功能，参与关节炎血管并发症的发生。本项目将应用HK基因敲除小鼠，建立自发性关节炎合并动脉粥样硬化疾病模型，结合病理组织学等方法，在体判定HKa是否抑制关节炎EPCs功能，阻碍损伤血管内皮修复从而加速动脉粥样硬化，并剖析其机制。这将为揭示RA与血管并发症的演变关系提供新的认识和研究思路。

Rheumatoid arthritis (RA) is a systemic autoimmune disease which is mainly characterized by destruction of articular structures. Cardiovascular and cerebrovascular diseases are major causes of mortality and morbidity in patients with RA, and most of them develope atherosclerosis (AS). However, the mechanisms underlying vascular complications remain largely unknown. It has been demonstrated that plasma kallikrein-kinin System (KKS) plays an important role in the pathogenesis of RA. We have recently reported that inhibition of KKS activation significantly suppressed synovial recruitment of endothelial progenitor cells (EPCs) and joint inflammation in arthritic animal model. Moreover the activation product of plasma KKS, called cleaved high molecular weight kininogen (HKa) induces EPC senescence in vitro. It has been suggested that vascular endothelium abnormality caused by (EPCs) dysfunction is closely related with the development of atherosclerosis in RA patients.We hypothesize that HKa inhibition of EPC function contributes to the vascular pathology in arthritis. In this proposal we will investigate the in vivo activities of HKa in inhibition of EPCs, by utilizing HK deficient mice based on spontaneous arthritis/atherosclerosis model, combined histologic approaches. We will determine the effects of HKa on EPC survival and vascular repair ability, test whether deficiency of HKa could prevents the development of atherosclerosis during the process of RA. Our study will reveal the role of HKa in the vascular pathology via inhibition of EPC function in the setting of arthritis, which will provide novel insight into the interplay between arthritis and the development of atherosclerosis.