Dual modulation of cell survival and cell death by β 2 -adrenergic signaling in adult mouse cardiac myocytes

Abstract

The goal of this study was to determine whether β 1 -adrenergic receptor (AR) and β 2 -AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One potential mechanism is that cardiac β 2 -AR can activate both G s and G i proteins, whereas cardiac β 1 -AR couples only to G s . To avoid complicated crosstalk between β-AR subtypes, we expressed β 1 -AR or β 2 -AR individually in adult β 1 /β 2 -AR double knockout mouse cardiac myocytes by using adenoviral gene transfer. Stimulation of β 1 -AR, but not β 2 -AR, markedly induced myocyte apoptosis, as indicated by increased terminal deoxynucleotidyltransferase-mediated UTP end labeling or Hoechst staining positive cells and DNA fragmentation. In contrast, β 2 -AR (but not β 1 -AR) stimulation elevated the activity of Akt, a powerful survival signal; this effect was fully abolished by inhibiting G i , G β γ , or phosphoinositide 3 kinase (PI3K) with pertussis toxin, βARK-ct (a peptide inhibitor of G β γ ), or LY294002, respectively. This indicates that β 2 -AR activates Akt via a G i -G β γ -PI3K pathway. More importantly, inhibition of the G i -G β γ -PI3K-Akt pathway converts β 2 -AR signaling from survival to apoptotic. Thus, stimulation of a single class of receptors, β 2 -ARs, elicits concurrent apoptotic and survival signals in cardiac myocytes. The survival effect appears to predominate and is mediated by the G i -G β γ -PI3K-Akt signaling pathway.