β-Adrenoceptor stimulation serves as the most powerful means to increase cardiac output in response to stress or exercise. However, sustained β-adrenoceptor stimulation promotes pathological cardiac remodeling such as myocyte hypertrophy and apoptosis, thus contributing to heart failure. Coexisting cardiac β-adrenoceptor subtypes, mainly β1- adrenoceptors and β2-adrenoceptors, activate different signaling cascades with β1-adrenoceptors coupling to Gs and β2-adrenoceptors coupling to Gs and Gi pathways. As a result, sustained β2-adrenoceptor stimulation protects cardiomyocytes against apoptosis via a Gi- phosphatidylinositol 3-kinase-protein kinase B pathway, whereas chronic β1-adrenoceptor stimulation induces myocyte hypertrophy and apoptosis by protein kinase A-independent activation of calmodulin kinase II signaling. These advances in our understanding of β-adrenoceptor subtype signaling identify the mechanisms that underlie the beneficial effects of β-adrenoceptor antagonists and delineate the rationale for combining β1-adrenoceptor blockade with β2-adrenoceptor activation as a potential therapy for heart failure.
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