1.

論文

論文
Seok, Young Mi ; Azam, Mohammed Ali ; Okamoto, Yasuo ; Sato, Atsushi ; Yoshioka, Kazuaki ; Maeda, Masataka ; Kim, In Kyeom ; Takuwa, Yoh
出版情報: Hypertension.  56  pp.934-941,  2010-11-01.  American Heart Association
URL: http://hdl.handle.net/2297/25788
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-depen dent MLC kinase activation, constitutes the major signaling mechanisms for vascular smooth muscle contraction. We recently 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
2.

論文

論文
Seok, Young Mi ; Choi, Young Whan ; Kim, Gyung-Duck ; Kim, Hye-Young ; Takuwa, Yoh ; Kim, In Kyeom
出版情報: Naunyn-Schmiedeberg's Archives of Pharmacology.  383  pp.45-56,  2011-01-01.  Springer Verlag (Germany)
URL: http://hdl.handle.net/2297/25789
概要: 金沢大学医薬保健研究域医学系<br />Gomisin A (GA) is an active ingredient of the fruits of Schisandra chinensis which has been wi dely used as a tonic in traditional Korean medicine. GA induces not only endothelium-dependent but also endothelium-independent relaxation in an isolated rat's thoracic aorta. This study was aimed to investigate the molecular mechanism by which GA induces endothelium-independent vasorelaxation. Rat aortic rings were denuded of endothelium, mounted in organ baths, and subjected to contraction or relaxation. We measured the amount of GTP RhoA as well as the phosphorylation level of 20 kDa myosin light chains (MLC20), myosin phosphatase-targeting subunit 1 (MYPT1) and protein kinase C-potentiated inhibitory protein for heterotrimeric myosin light-chain phosphatase of 17 kDa (CPI17). Pretreatment with GA dose-dependently inhibited the concentration-response curves in response to sodium fluoride (NaF) or thromboxane A2 agonist U46619, but not to phorbol 12, 13-dibutyrate (PDBu). GA decreased the activation of RhoA as well as the phosphorylation level of MLC20, MYPT1Thr855, and CPI17 induced by 8.0 mM NaF or 30 nM U46619. However, K+ channel blockers such as glibenclamide, apamin, or charybdotoxin did not affect the vascular relaxation induced by GA. Furthermore, GA did not affect the level of phosphorylation of CPI17 induced by PDBu. GA reduces vascular contraction through inhibition of RhoA/Rho-kinase pathway in endothelium-denuded rat aorta. © 2010 Springer-Verlag. 続きを見る
3.

論文

論文
Seok, Young Mi ; Choi, Young Whan ; Kim, Gyung-Duck ; Kim, Hye-Young ; Takuwa, Yoh ; Kim, In Kyeom
出版情報: Naunyn-Schmiedeberg's Archives of Pharmacology.  383  pp.45-56,  2011-01-01.  Springer-Verlag
URL: http://hdl.handle.net/2297/26244
概要: 金沢大学医薬保健研究域医学系<br />Gomisin A (GA) is an active ingredient of the fruits of Schisandra chinensis which has been wi dely used as a tonic in traditional Korean medicine. GA induces not only endothelium-dependent but also endothelium-independent relaxation in an isolated rat's thoracic aorta. This study was aimed to investigate the molecular mechanism by which GA induces endothelium-independent vasorelaxation. Rat aortic rings were denuded of endothelium, mounted in organ baths, and subjected to contraction or relaxation. We measured the amount of GTP RhoA as well as the phosphorylation level of 20 kDa myosin light chains (MLC20), myosin phosphatase-targeting subunit 1 (MYPT1) and protein kinase C-potentiated inhibitory protein for heterotrimeric myosin light-chain phosphatase of 17 kDa (CPI17). Pretreatment with GA dose-dependently inhibited the concentration-response curves in response to sodium fluoride (NaF) or thromboxane A2 agonist U46619, but not to phorbol 12, 13-dibutyrate (PDBu). GA decreased the activation of RhoA as well as the phosphorylation level of MLC20, MYPT1Thr855, and CPI17 induced by 8.0 mM NaF or 30 nM U46619. However, K+ channel blockers such as glibenclamide, apamin, or charybdotoxin did not affect the vascular relaxation induced by GA. Furthermore, GA did not affect the level of phosphorylation of CPI17 induced by PDBu. GA reduces vascular contraction through inhibition of RhoA/Rho-kinase pathway in endothelium-denuded rat aorta. © 2010 Springer-Verlag. 続きを見る
4.

論文

論文
Seok, Young Mi ; Choi, Young Whan ; Kim, Gyung-Duck ; Kim, Hye-Young ; Takuwa, Yoh ; Kim, In Kyeom
出版情報: Naunyn-Schmiedeberg's Archives of Pharmacology.  383  pp.45-56,  2011-01-01.  Springer-Verlag
URL: http://hdl.handle.net/2297/26530
概要: 金沢大学医薬保健研究域医学系<br />Gomisin A (GA) is an active ingredient of the fruits of Schisandra chinensis which has been wi dely used as a tonic in traditional Korean medicine. GA induces not only endothelium-dependent but also endothelium-independent relaxation in an isolated rat's thoracic aorta. This study was aimed to investigate the molecular mechanism by which GA induces endothelium-independent vasorelaxation. Rat aortic rings were denuded of endothelium, mounted in organ baths, and subjected to contraction or relaxation. We measured the amount of GTP RhoA as well as the phosphorylation level of 20 kDa myosin light chains (MLC20), myosin phosphatase-targeting subunit 1 (MYPT1) and protein kinase C-potentiated inhibitory protein for heterotrimeric myosin light-chain phosphatase of 17 kDa (CPI17). Pretreatment with GA dose-dependently inhibited the concentration-response curves in response to sodium fluoride (NaF) or thromboxane A2 agonist U46619, but not to phorbol 12, 13-dibutyrate (PDBu). GA decreased the activation of RhoA as well as the phosphorylation level of MLC20, MYPT1Thr855, and CPI17 induced by 8.0 mM NaF or 30 nM U46619. However, K+ channel blockers such as glibenclamide, apamin, or charybdotoxin did not affect the vascular relaxation induced by GA. Furthermore, GA did not affect the level of phosphorylation of CPI17 induced by PDBu. GA reduces vascular contraction through inhibition of RhoA/Rho-kinase pathway in endothelium-denuded rat aorta. © 2010 Springer-Verlag. 続きを見る