Effects of Angiotensin Type I Receptor Blockade on the Cardiac Raf/MEK/ERK Cascade Activated via Adrenergic Receptors

• Published in: Journal of Pharmacological Sciences Vol. 113; no. 3; pp. 224 - 233
• Main Authors: Zhang, Guo-Xing, Kimura, Shoji, Murao, Koji, Yu, Xiao, Obata, Koji, Matsuyoshi, Hiroko, Takaki, Miyako
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 2010; The Japanese Pharmacological Society; Elsevier
• Subjects: Adrenergic beta-Agonists - administration & dosage; Adrenergic beta-Agonists - adverse effects; Adrenergic beta-Agonists - pharmacology; angiotensin II; Angiotensin II Type 1 Receptor Blockers - adverse effects; Angiotensin II Type 1 Receptor Blockers - pharmacology; angiotensin-receptor blocker; Animals; Antihypertensive Agents - adverse effects; Antihypertensive Agents - pharmacology; Benzimidazoles - pharmacology; Cardiomegaly - chemically induced; Cardiomegaly - drug therapy; Cardiomegaly - metabolism; Heart Failure - drug therapy; Heart Ventricles - drug effects; Heart Ventricles - metabolism; isoproterenol; Isoproterenol - administration & dosage; Isoproterenol - adverse effects; Isoproterenol - pharmacology; Male; MAP Kinase Signaling System - drug effects; Mice; Mice, Inbred C57BL; Mice, Knockout; phenylephrine; Phosphorylation - drug effects; Proto-Oncogene Proteins c-raf - metabolism; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - metabolism; rap1 GTP-Binding Proteins - metabolism; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1 - genetics; Receptors, Adrenergic, beta - metabolism; signal transduction; Tetrazoles - pharmacology; angiotensin-receptor blocker; isoproterenol; signal transduction; phenylephrine; angiotensin II
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.09336FP

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.