Adrenergic Receptor Signaling Pathways in the Regulation of Apoptosis and Autophagy in the Heart

Abstract

Despite the discovery of several new therapeutic interventions, heart disease remains the number one cause of death worldwide. Many forms of heart disease are associated with loss of functional heart muscle cells, cardiac hypertrophy, remodeling and chamber dilation as well as deterioration in cardiac function. Significant changes in the levels of mediators regulating apoptosis and autophagy have been reported in both patients and experimental models of heart disease. Endogenous catecholamines, norepinephrine and epinephrine have been shown to play a critical role in cell death and pro-survival pathways in the heart by binding to β1-, β2- and α1- adrenergic receptors (ARs). While there is scant information on the mechanisms regulating cell death and pro-survival pathways, a deeper understanding of these processes and their interplay is essential for development of new therapies for patients suffering from heart disease. Here, we have briefly reviewed various signal transduction mechanisms linking adrenergic receptors with apoptosis and autophagy in the heart. Notably, elevated plasma levels of norepinephrine or β1-AR autoantibodies can induce apoptosis via stimulation of the β1-AR/cAMP/protein kinase A dependent and independent pathways and activation of β2- or α1-ARs can have pro-survival functions in cardiomyocytes. Whereas both AR agonists and antagonists can either increase or decrease autophagy depending on the cardiovascular cell type and experimental model system used. In addition, we have provided a comprehensive survey of the literature relevant to the effects of various adrenergic drugs on the signaling mechanisms regulating apoptosis and autophagy and discussed the relevance of these events in heart disease.