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

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.