| Project/Area Number |
15590230
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Kagawa University |
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Principal Investigator |
KIMURA Shoji Kagawa University, Faculty of Medicine, Dept of Pharmacology, Associate Professor, 医学部, 助教授 (30253264)
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| Co-Investigator(Kenkyū-buntansha) |
ABE Youichi Kagawa University, Faculty of Medicine, Dept of Pharmacology, Professor, 医学部, 教授 (10047227)
MIYATAKE Akira Kagawa University, Life Science Research Center, Associated Professor, 総合生命科学実験センター, 助教授 (80211598)
NISHIYAMA Akira Kagawa University, Faculty of Medicine, Dept of Pharmacology, Assistant, 医学部, 助手 (10325334)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Keywords | angiotensin / Hypertension / Superoxide / Ischemic-reperfudion injury / Mitochondria / Adrenergic receptor / Mitogen-activated protein kinase |
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| Research Abstract |
This study aimed to examine the involvement of mitochondria-derived reactive oxygen species (ROS) in the signaling pathway and the vasoconstrictor mechanism of Ang II. Using 5-hydroxydecanoate (5-HD ; a specific inhibitor of mitochondrial ATP-sensitive potassium channels (mitoKATP)) and tempol (a superoxide dismutase mimetic), the effects of Ang II and diazoxide (a mitoKATP opener), were compared on redox-sensitive mitogen-activated protein kinase (MAPK) activation in rat vascular smooth muscle cells (RVSMC) in vitro and in rat aorta in vivo. Stimulation of RVSMC by Ang II or diazoxide increased phosphorylated MAPK (ERK1/2,p38 and JNK) as well as superoxide production ; which were then suppressed by 5-HD pretreatment in a dose dependent manner, except for ERK1/2 activation by Ang II. The same events were reproduced in rat aorta in vivo. Ang II like diazoxide depolarized the mitochondrial membrane potential (ΔΨ_M) of RVSMC, which was inhibited by 5-HD. 5-HD did not modulate Ang II induc
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ed calcium mobilization in RVSMC and did not affect on the vasoconstrictor effect in either acute or chronic phases of Ang II induced hypertension. These results reveal that Ang II stimulates mitochondrial ROS production through the opening of mitoKATP in the vasculature, leading to reduction of ΔΨ_M and redox-sensitive activation of MAPK ; however, generated ROS from mitochondria do not contribute to Ang II-induced vasoconstriction. See Hypertension 2005;45(3):438-44 and Hypertension 2005 (in press) in detail. The related articles also demonstrated as shown below ;
1)Acute administration of Ang II and phenylephrine to conscious rats provoked redox-sensitive activation of MAPK in the heart and aorta. (Hypertension. 2004;43:117-24, J Pharmacol Sci. 2004;96;406-10)
2)The mechanisms of Ang II induced vasoconstriction may shift from being non-sensitive to ROS to sensitive within 12 hours. (J Hypertens. 2004;22:2161-8.)
3)(β-adrenoceptor stimulation provokes cardiac oxidative stress, while the generated ROS are responsible for the activation of MAPK cascade. (Cardiovasc Res. 2005;65:230-8.) Less
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