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Enhanced Ca2++-dependent activation of phosphoinositide 3-kinase class IIα isoform-Rho axis in blood vessels of spontaneously hypertensive rats

フォーマット:
論文
責任表示:
Seok, Young Mi ; Azam, Mohammed Ali ; Okamoto, Yasuo ; Sato, Atsushi ; Yoshioka, Kazuaki ; Maeda, Masataka ; Kim, In Kyeom ; Takuwa, Yoh
言語:
英語
出版情報:
American Heart Association, 2010-11-01
著者名:
Seok, Young Mi
Azam, Mohammed Ali
Okamoto, Yasuo
Sato, Atsushi
Yoshioka, Kazuaki
Maeda, Masataka
Kim, In Kyeom
Takuwa, Yoh
続きを見る
掲載情報:
Hypertension
ISSN:
0194-911x  CiNii Articles  Webcat Plus  JAIRO
巻:
56
通号:
5
開始ページ:
934
終了ページ:
941
バージョン:
author
概要:
金沢大学医薬保健研究域医学系<br />Rho-mediated inhibition of myosin light chain (MLC) phosphatase (MLCP), together with Ca-dependent MLC kinase activation, constitutes the major signaling mechanisms for vascular smooth muscle contraction. We recent ly unveiled the involvement of Ca-induced, phosphoinositide 3-kinase (PI3K) class IIα isoform (PI3K-C2α)-dependent Rho activation and resultant Rho kinase-dependent MLCP suppression in membrane depolarization- and receptor agonist-induced contraction. It is unknown whether Ca- and PI3K-C2α- dependent regulation of MLCP is altered in vascular smooth muscle of hypertensive animals and is involved in hypertension. Therefore, we studied the role of the Ca-PI3K-C2α-Rho-MLCP pathway in spontaneously hypertensive rats (SHRs). PI3K-C2α was readily detected in various vascular beds of Wistar-Kyoto rats and activated by high KCl. High KCl also stimulated vascular Rho activity and phosphorylation of the MLCP regulatory subunit MYPT1 at Thr in a PI3K inhibitor wortmannin-sensitive manner. In mesenteric and other vessels of SHRs at the hypertensive but not the prehypertensive stage, the activity of PI3K-C2α but not class I PI3K p110α was elevated with concomitant rises of Rho activity and Thr-phosphorylation of MYPT1, as compared with normotensive controls. Infusion of the Ca channel antagonist nicardipine reduced blood pressure with suppression of vascular activity of PI3K-C2α-Rho and phosphorylation of MYPT1 in hypertensive SHRs. Infusion of wortmannin lowered blood pressure with inhibition of PI3K-C2α-Rho activities and MYPT1 phosphorylation in hypertensive SHRs. These observations suggest that an increased activity of the Ca-PI3K-C2α-Rho signaling pathway with resultant augmented MLCP suppression contributes to hypertension in SHRs. The Ca- and PI3K-C2α-dependent Rho stimulation in vascular smooth muscle may be a novel, promising target for treating hypertension. © 2010 American Heart Association, Inc. 続きを見る
URL:
http://hdl.handle.net/2297/25788

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