The β2-Adrenergic Receptor Delivers an Antiapoptotic Signal to Cardiac Myocytes Through Gi-Dependent Coupling to Phosphatidylinositol 3′-Kinase

Abstract

Abstract—Recent studies have shown that chronic β-adrenergic receptor (β-AR) stimulation alters cardiac myocyte survival in a receptor subtype-specific manner. We examined the effect of selective β 1- and β 2-AR subtype stimulation on apoptosis induced by hypoxia or H 2 O 2 in rat neonatal cardiac myocytes. Although neither β 1- nor β 2-AR stimulation had any significant effect on the basal level of apoptosis, selective β 2-AR stimulation protected myocytes from apoptosis. β 2-AR stimulation markedly increased mitogen-activated protein kinase/extracellular signal–regulated protein kinase (MAPK/ERK) activation as well as phosphatidylinositol-3′-kinase (PI-3K) activity and Akt/protein kinase B phosphorylation. β 1-AR stimulation also markedly increased MAPK/ERK activation but only minimally activated PI-3K and Akt. Pretreatment with pertussis toxin blocked β 2-AR–mediated protection from apoptosis as well as the β 2-AR–stimulated changes in MAPK/ERK, PI-3K, and Akt/protein kinase B. The selective PI-3K inhibitor, LY 294002, also blocked β 2-AR–mediated protection, whereas inhibition of MAPK/ERK activation at an inhibitor concentration that blocked agonist-induced activation but not the basal level of activation had no effect on β 2-AR–mediated protection. These findings demonstrate that β 2-ARs activate a PI-3K–dependent, pertussis toxin–sensitive signaling pathway in cardiac myocytes that is required for protection from apoptosis-inducing stimuli often associated with ischemic stress.