The β 2 -Adrenergic Receptor Delivers an Antiapoptotic Signal to Cardiac Myocytes Through G i -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.