Distinct β-adrenergic receptor subtype signaling in the heart and their pathophysiological relevance

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Journal Title:
Volume 56, Issue 01, 2004
Key Word:
β-adrenergic receptors;heart;signal transduction

Abstract: In the heart, stimulation of β-adrenergic receptors (βAR) serves as the most powerful means to increase cardiac contractility and relaxation in response to stress or a "fight-or-flight" situation. However, sustained β-adrenergic stimulation promotes pathological cardiac remodeling such as myocyte hypertrophy, apoptosis and necrosis, thus contributing to the pathogenesis of chronic heart failure. Over the past decade, compelling evidence has demonstrated that coexisting cardiac βAR subtypes, mainly β1AR and β2AR, activate markedly different signaling cascades. As a result, acute β1AR stimulation activates the Gs-adenylyl cyclase-cAMP-PKA signaling that can broadcast throughout the cell, whereas β2AR-evoked cAMP signaling is spatially and functionally compartmentalized, due to concurrent Gi activation. Chronic stimulation of β1AR and β2AR elicits opposing effects on the fate of cardiomyocytes: β1AR induces hypertrophy and apoptosis; but β2AR promotes cell survival. The cardiac protective effect of β2AR is mediated by a signaling pathway sequentially involving Gi, Gβγ, PI3K and Akt. Unexpectedly,β1AR-induced myocyte hypertrophy and apoptosis are independent of the classic cAMP/PKA pathway, but require activation of Ca2+/calmodulin-dependent kinase Ⅱ (CaMK Ⅱ ). The outcomes of cardiac-specific transgenic overexpression of either βAR subtype in mice have reinforced the fundamentally different functional roles of these βAR subtypes in governing cardiac remodeling and performance. These new insights regarding βAR subtype stimulation not only provide clues as to cellular and molecular mechanisms underlying the beneficial effects of βAR blockers in patients with chronic heart failure, but also delineate rationale for combining selective β1AR blockade with moderate β2AR activation as a potential novel therapy for the treatment of chronic heart failure.

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