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

血栓形成是内膜增厚发展的关键事件，内膜增厚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，TF在动脉粥样硬化病变有助于动脉粥样硬化的形成。虽然天然TF本身没有内在的蛋白酶活性，但TF和FVIIa的双分子复合物导致FVIIa催化结构域的增强并激活FIX和FX，这导致凝血酶产生。PAR包含七跨膜G蛋白偶联受体家族。丝氨酸蛋白酶在N-末端的切割激活PAR，然后产生新的拴系配体，其与细胞外环-2内的受体相互作用。迄今已鉴定出以下PAR受体：PAR 1、PAR 2、PAR 3和PAR 4。凝血酶是PAR 1、PAR 3和PAR 4的强有力的激活剂，但其他蛋白酶也可以切割这些受体，因此可能在生理上有助于它们的功能。几种胰蛋白酶 ...更多信息 N-样丝氨酸蛋白酶，包括胰蛋白酶、类胰蛋白酶和FVIIa和Xa，激活PAR 2，但凝血酶不激活。这些PAR激活蛋白酶，尤其是凝血剂，介导止血和血栓形成的关键反应，以及组织损伤引发的炎症和增殖反应。尽管PAR在正常或病理状态下可能发挥重要作用，但哪些蛋白酶和PAR在特定的细胞过程中起作用仍不清楚。表1显示了PAR 2在心血管系统中的作用。由PAR 1、3和4介导的凝血酶信号传导有助于动脉粥样硬化形成（综述见60），但PAR 2在动脉粥样硬化病变中的作用尚未阐明。有报道表明，PAR 2在主动脉壁中表达，并且在球囊损伤后增加。我们在冠状动脉粥样硬化病变的内膜和中膜以及培养的主动脉平滑肌细胞中鉴定了PAR 2免疫反应性。我们还报道了暴露的系留PAR 2配体的PAR 2活化肽诱导SMC迁移，这与TF/FVIIa复合物和血小板衍生生长因子-BB诱导的相当。已经在PAR 2缺陷小鼠中评估了PAR 2对炎症反应的贡献。进一步的检查，特别是心血管系统，包括动脉粥样硬化形成，应该很快证实PAR 2在动脉粥样硬化中的作用。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