Dual modulation of cell survival and cell death by β2-adrenergic signaling in adult mouse cardiac myocytes

The goal of this study was to determine whether beta (1)-adrenergic receptor (AR) and beta (2)-AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One potential mechanism is that cardiac beta (2)-AR can activate both G(s) and G(i) proteins, whereas cardiac beta (1)-AR couples only to G(s). To avoid complicated crosstalk between beta -AR subtypes, we expressed beta (1)-AR or beta (2)-AR individually in adult beta (1)/beta (2)-AR double knockout mouse cardiac myocytes by using adenoviral gene transfer. Stimulation of beta (1)-AR, but not beta (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, beta (2)-AR (but not beta (1)-AR) stimulation elevated the activity of Akt, a powerful survival signal; this effect was fully abolished by inhibiting G(i), C-beta gamma, or phosphoinositide 3 kinase (PI3K) with pertussis toxin, beta ARK-ct (a peptide inhibitor of G(beta gamma)), or LY294002, respectively. This indicates that beta (2)-AR activates Akt via a G(i)-G(beta gamma)-PI3K pathway. More importantly, inhibition of the G(i)-G beta gamma -PI3K-Akt pathway converts beta (2)-AR signaling from survival to apoptotic, Thus, stimulation of a single class of receptors, beta (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(beta gamma)-PI3K-Akt signaling pathway.