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

蛋白酶激活受体（PAR）-2在动脉硬化发病机制和进展中的作用

• 批准号: 16590321
• 负责人: MARUTSUKA Kousuke
• 金额: $ 2.3万
• 依托单位: University of Miyazaki
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590321/
• 关键词: PAR2; Thrombus formation; animal model of arteriosclerosis; Bone marrow transplantation; Localization; 内膜肥厚

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

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。包括我们在内的许多研究都表明，动脉粥样硬化病变中的TF有助于动脉粥样硬化的发生。虽然天然TF本身没有内在的蛋白酶活性，但TF和FVIIa的双分子复合物会增强FVIIa的催化结构域，激活FIX和FX，从而产生凝血酶。PARs由7个跨膜g蛋白偶联受体组成。丝氨酸蛋白酶在n端裂解激活PARs，然后产生一个新的拴链配体，与细胞外环-2内的受体相互作用。目前已知的PAR受体有：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切割这些受体，因此可能在生理上有助于它们的功能。更多的n样丝氨酸蛋白酶，包括胰蛋白酶、胰蛋白酶、FVIIa和Xa，可以激活PAR2，但凝血酶不能。这些par活化蛋白酶，尤其是凝血剂，介导了对止血和血栓形成至关重要的反应，以及组织损伤引发的炎症和增殖反应。尽管PAR可能在正常或病理状态下发挥重要作用，但蛋白酶和PAR在特定细胞过程中的作用尚不清楚。表1显示了PAR2在心血管系统中的作用。由pars1、3和4介导的凝血酶信号有助于动脉粥样硬化（见60），但PAR2在动脉粥样硬化病变中的参与尚未阐明。一些报道表明，PAR2在主动脉壁表达，球囊损伤后增加。我们在冠状动脉粥样硬化病变的内膜和介质以及培养的主动脉SMCs中发现了PAR2免疫反应性。我们还报道了暴露的拴系PAR2配体的PAR2激活肽诱导SMC迁移，这与TF/FVIIa复合物和血小板衍生生长因子- bb诱导的迁移相当。PAR2对炎症反应的贡献已经在PAR2缺陷小鼠中进行了评估。进一步的检查，特别是心血管系统包括动脉粥样硬化的检查，应该很快确认PAR2在动脉粥样硬化中的作用。少

项目成果

Adrenomedullin administration immediately after myocardial infarction ameliorates progression of heart failure in rats

• DOI: 10.1161/01.cir.0000136085.34185.83
• 发表时间: 2004-07-27
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Nakamura, R;Kato, J;Eto, T
• 通讯作者: Eto, T

動脈硬化性血栓の成長における血管壁の凝固活性と血流の関与

血管壁凝血活性和血流参与动脉粥样硬化血栓的生长

• 发表时间: 2006
• 期刊: 日本血栓止血学会雑誌 17(1)
• 作者: Kitazawa S;Kitazawa R.;山下 篤
• 通讯作者: 山下 篤

Possible contribution of C-reactive protein within coronary plaque to increasing its own plasma levels across coronary circulation

• DOI: 10.1016/j.amjcard.2003.11.030
• 发表时间: 2004-03-01
• 期刊: AMERICAN JOURNAL OF CARDIOLOGY
• 影响因子: 2.8
• 作者: Ishikawa, T;Imamura, T;Eto, T
• 通讯作者: Eto, T

Inhibition of 5-hydroxytryptamine receptor prevents occlusive thrombus formation on neointima of the rabbit femoral artery.

• 发表时间: 2006
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: K. Nishihira;A. Yamashita;N. Tanaka;R. Kawamoto;T. Imamura;R. Yamamoto;T. Eto;Y. Asada

Adrenomedullin alleviates not only neointimal formation but also perivascular hyperplasia following arterial injury in rats.

肾上腺髓质素不仅可以减轻大鼠动脉损伤后的新内膜形成，还可以减轻血管周围增生。

• 发表时间: 2005
• 期刊: European Journal of Pharmacology 508(1-3)
• 作者: Tsuruda T;Kato J;Matsui E;Hatakeyama K;Masuyama H;Imamura T;Kitamura K;Asada Y;Eto T
• 通讯作者: Eto T