The role of protease activated receptor (PAR)-2 in pathogenesis and progression of arteriosclerosis

血栓形成是动脉内膜增厚发展过程中的关键事件，被认为是动脉粥样硬化斑块形成的早期阶段。许多研究，包括我们的研究，已经证明动脉粥样硬化病变中的转铁蛋白参与了动脉粥样硬化的形成。尽管天然转铁蛋白本身没有内在的蛋白酶活性，但转铁蛋白和FVIIa的双分子复合体导致FVIIa催化结构域的增强，并激活FIX和FX，从而导致凝血酶的产生。PARs由七个跨膜G蛋白偶联受体家族组成。N-末端的丝氨酸蛋白酶裂解激活PARS，然后产生一种新的系链配体，与细胞外环-2内的受体相互作用。到目前为止，已鉴定出以下PAR受体：PAR1、PAR2、PAR3和PAR4。凝血酶是PAR1、PAR3和PAR4的强大激活剂，但其他蛋白酶也可以裂解这些受体，因此可能在生理上对它们的功能做出贡献。几种胰酶…更多的类n丝氨酸蛋白酶，包括胰酶、胰蛋白酶、FVIIa和Xa，可以激活PAR2，但凝血酶不能。这些激活PAR的蛋白水解酶，特别是凝血剂，介导了对止血和血栓形成至关重要的反应，以及由组织损伤引发的炎症和增殖性反应。虽然PARs可能在正常或病理状态下发挥重要作用，但在特定的细胞过程中，哪种蛋白水解酶(S)和PAR(S)的作用尚不清楚。表1显示了PAR2在心血管系统中的作用。凝血酶信号通路由PAR1、PAR3和PAR4介导，参与动脉粥样硬化的形成(见文献60)，但PAR2在动脉粥样硬化病变中的作用尚不清楚。已有研究表明PAR2在主动脉壁有表达，球囊损伤后PAR2表达增加。我们发现PAR2免疫反应性存在于冠状动脉粥样硬化病变的内膜和中层，也存在于培养的主动脉平滑肌细胞中。我们还报道，暴露的PAR2配体上的PAR2激活肽可以诱导SMC迁移，这与TF/FVIIa复合体和血小板衍生生长因子-BB诱导的迁移作用相当。已经在PAR2缺陷小鼠中评估了PAR2对炎症反应的贡献。进一步的检查，特别是包括动脉粥样硬化在内的心血管系统的检查，应该很快就能证实PAR2在动脉粥样硬化中的作用。较少

Thrombus formation is a key event in the development of intimal thickening, which is considered to comprise the early stage of atherosclerotic plaque formation. Many studies, including ours have demonstrated that TF in atherosclerotic lesions contributes to atherogenesis. Although native TF itself has no intrinsic protease activity, the bimolecular complex of TF and FVIIa results in enhancement of the FVIIa catalytic domain and activates FIX and FX, which leads to thrombin generation. PARs comprise a family of seven-transmembrane G-protein-coupled receptors. Serine protease cleavage at the N-terminus activates PARs, which then generates a new tethered ligand that interacts with the receptors within extracellular loop-2. The following PAR receptors have been identified to date : PAR1, PAR2, PAR3 and PAR4. Thrombin is a powerful activator of PAR1, PAR3 and PAR4, but other proteases can also cleave these receptors and thus might physiologically contribute to their function. Several trypsi … More n-like serine proteases, including trypsin, tryptase, and FVIIa and Xa, activate PAR2, but thrombin does not. These PAR-activating proteases, especially the coagulants, mediate the responses that are critical for hemostasis and thrombosis, as well as inflammatory and proliferative reactions triggered by tissue damage. Although PARs might play important roles in normal or pathological states, which protease(s) and PAR(s) function in specific cellular processes remain unclear. Table 1 shows the roles of PAR2 in the cardiovascular system. Thrombin signaling, mediated by PARs 1, 3 and 4 contributes to atherogenesis (reviewed in 60), but the participation of PAR2 in atherosclerotic lesions has not been elucidated. Some reports have demonstrated that PAR2 is expressed in aortic walls and increases after balloon injury. We identified PAR2 immunoreactivity in the intima and media of coronary atherosclerotic lesions and also in cultured aortic SMCs. We also reported that the PAR2-activating peptides of exposed tethered PAR2 ligand, induce SMC migration, which is comparable to that induced by TF/FVIIa complex and platelet-derived growth factor-BB. The contribution of PAR2 to inflammatory responses has been evaluated in PAR2-deficient mice. Further examination, especially of the cardiovascular system including atherogenesis, should confirm the role of PAR2 in atherosclerosis soon. Less