| Co-Investigator(Kenkyū-buntansha) |
ASADA Yujiro University of Miyazaki, Faculty of Medicine, Professor, 医学部, 教授 (70202588)
HATAKEYAMA Kinta University of Miyazaki, Faculty of Medicine, Assistant professor, 医学部, 講師 (60325735)
YAMASHITA Atsushi University of Miyazaki, Faculty of Medicine, Research associate, 医学部, 助手 (90372797)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
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
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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
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