Effects of Angiotensin Type I Receptor Blockade on the Cardiac Raf/MEK/ERK Cascade Activated via Adrenergic Receptors
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- Zhang Guo-Xing
- Department of Physiology II, Nara Medical University, Japan
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- Kimura Shoji
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Japan
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- Murao Koji
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Japan
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- Yu Xiao
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Japan Laboratory of Cellular and Molecular Tumor Immunology, Medical College, Soochow University, China
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- Obata Koji
- Department of Physiology II, Nara Medical University, Japan
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- Matsuyoshi Hiroko
- Department of Physiology II, Nara Medical University, Japan
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- Takaki Miyako
- Department of Physiology II, Nara Medical University, Japan
Bibliographic Information
- Other Title
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- Effects of angiotensin type 1 receptor blockade on the cardiac Raf/MEK/ERK cascade activated via adrenergic receptors
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Abstract
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.
Journal
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- Journal of Pharmacological Sciences
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Journal of Pharmacological Sciences 113 (3), 224-233, 2010
The Japanese Pharmacological Society
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Details 詳細情報について
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- CRID
- 1390001205179804032
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- NII Article ID
- 10029889243
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- NII Book ID
- AA11806667
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- ISSN
- 13478648
- 13478613
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- NDL BIB ID
- 10755962
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- CiNii Articles
- KAKEN
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- Abstract License Flag
- Disallowed