Effects of Angiotensin Type I Receptor Blockade on the Cardiac Raf/MEK/ERK Cascade Activated via Adrenergic Receptors
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概要
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A close interaction between adrenergic nerves and angiotensin systems has been documented. The present study was designed to investigate the mechanisms of angiotensin-receptor blocker (ARB) suppression of β-adrenergic receptor stimulation–induced cardiac hypertrophy. Chronic isoproterenol (ISO)–induced cardiac hypertrophy was inhibited in wild-type mice and AT1aR−/− mice treated with the ARB Candesartan (CV11974). Acute ISO–induced increase in phosphorylation levels of ERK MAPK was completely inhibited and increases in phosphorylation levels of p38 and JNK MAPKs were partially suppressed in both types of mice. Analysis of the activity of the small GTPase–regulating protein Raf indicated that the mechanisms by which ARB inhibits the Raf/MEK/ERK pathway under β-adrenergic receptor stimulation basically depended on changes in the binding activities of Ras (stimulatory to Raf cascade) and Rap-1 (inhibitory to Raf cascade). Binding activities of Ras and Rap-1 in the heart were markedly augmented by ISO, whereas ARB suppressed only Ras, but not Rap-1, binding activity. Raf immunoprecipitation results confirmed that ISO-induced increases in its association with total and phosphorylated forms of MEK were completely normalized by ARB. 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.
著者
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木村 正司
Department Of Pharmacology Kagawa Medical University
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KIMURA Shoji
Department of Pharmacology, Kagawa University Medical School
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ZHANG Guo-Xing
Department of Pharmacology, Kagawa University Medical School
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木村 正司
香川医大・薬理
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Obata Koji
Department of Phamacology, Achigakuin University School of Dentistry
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Kagami Shoji
Department Of Pediatrics The University Of Tokushima Graduate School Of Medical Sciences
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MURAO Koji
Division of Endocrinology and Metabolism, Haematology, Rheumatology and Respiratory Medicine, Depart
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TAKAKI Miyako
Department of Physiology II, Nara Medical University
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Obata Koji
Department Of Information Engineering Nagoya University
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MATSUYOSHI Hiroko
Department of Physiology II, Nara Medical University
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Yu Xiao
Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kaga
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Matsuyoshi Hiroko
Department Of Physiology Ii Nara Medical University
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Kimura Shoji
Department Of Agricultural Chemistry Faculty Of Agriculture Utsunomiya University
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Takaki Miyako
Department Of Physiology Ii Nara Medical University
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Guoxing Zhang
Department Of Pharmacology Kagawa Medical University
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Zhang Guo-xing
Department Of Physiology Ii Nara Medical University
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Zhang Guo-xing
Department Of Pharmacology Kagawa Medical University
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Murao Koji
Division Of Endocrinology And Metabolism Department Of Internal Medicine Kagawa University
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Kimura S
The Department Of Pharmacology Kagawa Medical School
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Yu Xiao
Division Of Endocrinology And Metabolism Department Of Internal Medicine Faculty Of Medicine Kagawa
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Murao Koji
Division Of Endocrinology And Metabolism Department Of Internal Medicine Faculty Of Medicine Kagawa
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