2006 Fiscal Year Final Research Report Summary
Interaction between AT1 and β-adrenergic receptors affects redox-sensitive intracellular signal transduction in heart
| Project/Area Number |
17590220
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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, Department of Pharmacology, Assistant Professor, 医学部, 助教授 (30253264)
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| Co-Investigator(Kenkyū-buntansha) |
OHMORI Kouji Kagawa University, Faculty of Medicine, Assistant Professor, 医学部, 助教授 (00263913)
NISHIYAMA Akira Kagawa University, Faculty of medicine, Professor, 医学部, 教授 (10325334)
MIYATAKE Akira Kagawa University, Life Science Research Center, Assistant Professor, 総合生命科学実験センター, 助教授 (80211598)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Angiotensin / Adrenergic receptor |
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| Research Abstract |
Elevated activities of the sympathetic nerve and renin-angiotensin systems are common features of heart failure. This study aimed to examine the involvement of interaction between AT1 and β-adrenergic receptors in redox-sensitive signal transduction in the failing heart. Chronic isoproterenol (ISO) infusion to mice caused concentric cardiac hypertrophy, accompanied by enhancement of cardiac collagen accumulation, lipid peroxidation, superoxide generation and NADPH oxidase activity. The AT1a and β-1,2 receptor mRNA expressions were down-regulated in the heart of ISO-infused mice. Simultaneous treatment of ARB markedly suppressed cardiac mass enlargement as well as increases of oxidative indicators without any effects on heart rate. The ATla receptor contribution to ISO-induced cardiac hypertrophy was reproduced in AT1aR-/-mice. These data suggest that the AT1 receptor plays a crucial role in the development of cardiac hypertrophy and oxidative stress under excessive β-adrenergic stimula
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tion, and that ARB treatment is beneficial for sympatho-excitatory cardiac hypertrophy and failure in mice.
We also examined the effects of ARB on redox-sensitive activation of cardiac MAPK provoked by acute administration of ISO, resulting in the suppressive effects of ARB on ISO-induced MAP kinase activation. Analysis of the small GTPase regulating Raf activity indicated that the mechanism by which ARB inhibits the Raf/MEK/ERK pathway under β-adrenergic receptor stimulation was basically dependent on changes in the activities of Ras (stimulatory) and Rap-1 (inhibitory to Raf cascade). Activities of Ras and Rap-1 in the heart were markedly augmented by ISO, whereas ARB suppressed only Ras activity, but not Rap-1 activity. Raf immunoprecipitation experiments confirmed that increases in its association with total and phosphorylated forms of MEK induced by ISO were completely normalized by ARB treatment. These results might provide a molecular basis for the beneficial effects of AT1 receptor antagonists on cardiac remodeling and functions in patients with sympatho-excitatory heart failure. Less
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[Journal Article] Effects of adrenomedullin on cardiac oxidative stress and collagen accumulation in aldosterone-dependent malignant hypertensive rats.2006
Author(s)
Rahman M, Nishiyama A, Guo P, Nagai Y, Zhang GX, Fujisawa Y, Fan YY, Kimura S, Hosomi N, Omori K, Abe Y, Kohno M.
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Journal Title
J Pharmacol Exp Ther. 318
Pages: 1323-1329
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Augmentation of intrarenal angiotensin II levels in uninephrectomized aldosterone/salt-treated hypertensive rats; renoprotective effects of an ultrahigh dose of olmesartan.2006
Author(s)
Fan YY, Baba R, Nagai Y, Miyatake A, Hosomi N, Kimura S, Sun GP, Kohno M, Fujita M, Abe Y, Nishiyama A.
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Journal Title
Hypertens Res. 29
Pages: 169-78
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Contribution of reactive oxygen species to the pathogenesis of left ventricular failure in Dahl salt-sensitive hypertensive rats : effects of angiotensin II blockade.2006
Author(s)
Guo P, Nishiyama A, Rahman M, Nagai Y, Noma T, Namba T, Ishizawa M, Murakami K, Miyatake A, Kimura S, Mizushige K, Abe Y, Ohmori K, Kohno M.
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Journal Title
J Hypertens. 24
Pages: 1097-1104
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Synergistic effect of mechanical stretch and angiotensin II on superoxide production via NADPH oxidase in vascular smooth muscle cells.2006
Author(s)
Hitomi H, Fukui T, Moriwaki K, Matsubara K, Sun GP, Rahman M, Nishiyama A, Kiyomoto H, Kimura S, Ohmori K, Abe Y, Kohno M.
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Journal Title
J Hypertens. 24
Pages: 1089-1095
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Involvements of Rho-kinase and TGF-beta pathways in aldosterone-induced renal injury.2006
Author(s)
Sun GP, Kohno M, Guo P, Nagai Y, Miyata K, Fan YY, Kimura S, Kiyomoto H, Ohmori K, Li DT, Abe Y, Nishiyama A.
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Journal Title
J Am Soc Nephrol. 17
Pages: 2193-2201
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] D-allose, an all-cis aldo-hexose, suppresses development of salt induced hypertension in Dahl rats.2005
Author(s)
Kimura S, Zhang GX, Nishiyama A, Nagai Y, Nakagawa T, Miyanaka H, Fujisawa Y, Miyatake A, Nagai T, Tokuda M, Abe Y.
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Journal Title
J Hypertens. 23
Pages: 1887-1894
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Aldosterone stimulates collagen gene expression and synthesis via activation of ERK1/2 in renal fibroblasts.2005
Author(s)
Nagai Y, Miyata K, Sun GP, Rahman M, Kimura S, Miyatake A, Kiyomoto H, Kohno M, Abe Y, Yoshizumi M, Nishiyama A.
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Journal Title
Hypertension. 46
Pages: 1039-1045
Description
「研究成果報告書概要(欧文)」より
