β-Adrenergic Receptors Cooperate With Transcription Factors

Abstract

Through their wide tissue/cellular distribution, β-adrenoceptors are key regulators of cardiovascular function and remodeling. Classically, beta1- and beta2-adrenoceptors positively influence all aspects of cardiac contractility through G-α-s coupling to adenylyl cyclase and cAMP/protein kinase A phosphorylation of critical effectors of excitation-contraction (EC) coupling,1 whereas β3-adrenoceptors exert antipathetic effects, thereby attenuating those of B1-2AR stimulation.2,3 B1-2ARs are also known to initiate signaling that is independent of protein kinase A/cAMP and involves β-arrestin–dependent activation of extracellular signal-regulated kinases. Moreover, like many G-protein–coupled receptors, B1-2ARs can transactivate receptor tyrosine kinases, for example, epidermal growth factor receptor, thereby producing wider effects on cellular growth and survival.4 Article see p 48 In addition to acute regulation of EC coupling, catecholamines, like many neurohormones, exert profound effects on tissue remodeling, which involves engagement of specific transcription programs, leading to hypertrophy, fibrosis, and angiogenesis, but also profound changes in cell metabolism or survival, all of which participate in the initial adaptation to cardiac stress but eventually culminate in the chronic deterioration of cardiac function.5 Extensive experimental work has led to the identification of the signaling pathways driving the underlying transcriptional changes, including through epigenetic regulation.6 The traditional view has kept these 2 phenomena relatively apart, with little interplay between them. More recently, attention has been focused on the activation of transcription pathways as a consequence of ionic derangements (ie, changes in intracellular Ca2+ concentrations) in specific subcellular compartments, leading to activation of Ca2+-responsive pathways such as calcium/calmodulin-dependent protein kinase or calcineurin–nuclear factor of activated T cells.7,8 In addition, the stressed myocardium produces and is responsive to an array of paracrine signaling molecules, including growth factors and cytokines.9 These in turn modulate tissue remodeling and cell survival through activation of another class of receptors, …