Interaction between AT1 and β-adrenergic receptors affects redox-sensitive intracellular signal transduction in heart

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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 … More 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