| Co-Investigator(Kenkyū-buntansha) |
TANABE Yoshiyuki Ph. D., University of Shizuoka, Assistant to Professor Nakayama, 薬学部, 助手 (10275109)
OBARA Kazuo Ph. D., University of Shizuoka, Lecturer, 薬学部, 講師 (60117611)
ISHIKAWA Tomohisa Ph. D., Department of Pharmacology, Faculty of Pharmacertical Sciences, University of Shizuoka, Associate Professor, 薬学部, 助教授 (10201914)
ASANO Toshio Ph. D., Asai Kasei Co., Ltd., Director, ライフサイエンス総合研究所, 所長
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| Research Abstract |
<Purpose> Cardiovascular systems including blood vessels and heart are always subjected to hemodynamic stresses such as blood pressure and blood flow. We studied the mechanism of mechanotransduction of vascular tissues with special regard to the interactive role of tyrosine kinase, protein kinase C, and Rho/Rho kinase systems. We summarize herewith our results as following:
<Results and Discussion> (1) Pharmacological characteristics of mechanosensor molecules
We investigated two pathways transforming mechanical force to intracellular signaling. 1) Gadolinium ion-sensitive stretch-activated cation channel (SA): Myogenic contraction of canine cerebral artery in response to stretch was initiated by the following process; membrane was depolarized by activation of SA channel, and subsequent increase in cytosolic Ca occurred through L-type Ca channel, which led to opening of Ca-activated CI channel, and efflux of CI further depolarized the membrane. 2) RGD-peptide sensitive integrin: Stretch
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induced multiple phosphorylation of 20kd myosin light chain with low myogenic tone. The interactive role of tyrosine kinase, protein kinase C, and Rho/Rho kinase systems are in particular of importance to produce this multiple phosphorylation. Furthermore, we found that RGD-peptide sensitive and -insensitive pathways were involved in stretch-induced production of vasoconstrictor prostanoids, including untransformed prostaglandinH2, in rabbit pulmonary artery with endothelium.
(2) Chronophamacology of mechanotransduction
Increase in intraluminal pressure produced phasic and tonic myogenic contraction of rat cerebral artery. Rho/Rho kinase was involved in both phasic and tonic responses, whereas protein kinase C played a role in the tonic phase of myogenic contraction. Both kinases seem to act as a Ca sensitizer in the myogenic mechanism.
(3) Pasthophysiological aspects of mechanotransduction
1) Pulmonary hypertension: Hypobaric hypoxia induced pulmonary hypertension in mice. It is possible that pulmonary arteries are stretched excessively in pulmonary hypertension. Consequently, extracellular signal-regulated protein kinase (ERK1/2), an index of mechanotransduction, of murine lung was specifically activated. 2) Cerebral vasospasm after subarachnoid hemorrhage (CVS): CVS is considered to be elicited by erythrocyte-derived oxyhemoglobin, an oxygen stresser. We notice the relevance between CVS and the contractile and other responses to mechano-stress in terms of functional roles of tyrosine kinase, protein kinase C, and Rho/Rho kinase systems. Thus, the study of the mechanotransduction in cardiovascular system surely aids in clarifying the mechanisms underlying vasospastic episodes and the initiation of pathologic remodeling in cardiovascular diseases, and potentially has therapeutic consequences. Less
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