| Co-Investigator(Kenkyū-buntansha) |
HIRANO Katsuya KYUSHU UNIVERSITY, Graduate School of Medical Sciences, Lecturer, 大学院・医学研究院, 講師 (80291516)
NISHIMURA Junji KYUSHU UNIVERSITY, Graduate School of Medical Sciences, Associate Professor, 大学院・医学研究院, 助教授 (90237727)
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| Research Abstract |
Molecular mechanisms of vasospasm, especially the intracellular signaling network working for the Ca^<2+>-sensitization of smooth muscle cells, were determined. Following results were obtained. (1)Treatment of α-toxin-permeabilized rings with 1 mM ATPγS in the Ca^<2+>-free, ATP-free media enhanced the subsequent contraction induced by increment of Ca^<2+> concentration, and potentiated the Ca^<2+>-sensitivity, which was only partly inhibited by Rho-kinase inhibitor, Y-27632. We found a fundamental role of this new kinase other than Rho kinase in the regulation of the myosin phosphatase activity and myofilament Ca^<2+>-sensitivity in vascular smooth muscle. (2)Myosin phosphatase plays a critical role in potentiating the myofilament Ca^<2+>. The phosphatase activity is primary regulated by the 110kDa regulatory subunit, MYPT1. To determine the region of MYPT1 involved in regulation of myosin phosphatase in intact smooth muscle, we introduced MYPT1 fragments into the strips of porcine coronary artery as fusion protein with a cell penetrating peptide of HIV Tat protein(TAT-MYPT1, a construct containing Tat peptide and regions of MYPT1), and examined their effect on the contractility. We found that the region 1-296 is essential for this augmentation, while region 297-374 plays a supplemental role. (3)A role of thrombin and its receptor PAR1 in development of hypercontractility in subarachnoid hemorrhage was investigated in a rabbit double hemorrhage model. The subarachnoidal injection of autologous blood induced hyper-contractile response of the isolated basilar artery toward thrombin. The hyper-responsiveness was suggested to be due to the up-regulation and impairment of the desensitization of PAR1. The activation of thrombin due to hemorrhage was suggested to play an important role in induction of the hyper-responsiveness. Thrombin and PAR1 were thus suggested to be useful as a new therapeutic target in the management of SAH.
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