Dual Modulation of Cell Survival and Cell Death by β2-Adrenergic Signaling in Adult Mouse Cardiac Myocytes

• Published in: Proceedings of the National Academy of Sciences - PNAS 2001-02, Vol.98 (4), p.1607-1612
• Main Authors: Zhu, Wei-Zhong, Zheng, Ming, Koch, Walter J., Lefkowitz, Robert J., Kobilka, Brian K., Xiao, Rui-Ping
• Format: Article
• Language: English
• Subjects: Apoptosis; Biological Sciences; Cell death; DNA; DNA fragmentation; Heart; Infections; Modulated signal processing; Myocardium; Phosphorylation; Receptors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.98.4.1607

The goal of this study was to determine whether β1-adrenergic receptor (AR) and β2-AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One potential mechanism is that cardiac β2-AR can activate both Gsand Giproteins, whereas cardiac β1-AR couples only to Gs. To avoid complicated crosstalk between β-AR subtypes, we expressed β1-AR or β2-AR individually in adult β1/β2-AR double knockout mouse cardiac myocytes by using adenoviral gene transfer. Stimulation of β1-AR, but not β2-AR, markedly induced myocyte apoptosis, as indicated by increased terminal deoxynucleotidyltrans-ferase-mediated UTP end labeling or Hoechst staining positive cells and DNA fragmentation. In contrast, β2-AR (but not β1-AR) stimulation elevated the activity of Akt, a powerful survival signal; this effect was fully abolished by inhibiting Gi, Gβγor phosphoinositide 3 kinase (PI3K) with pertussis toxin, βARK-ct (a peptide inhibitor of Gβγ), or LY294002, respectively. This indicates that β2-AR activates Akt via a Gi-Gβγ-PI3K pathway. More importantly, inhibition of the Gi-Gβγ-PI3K-Akt pathway converts β2-AR signaling from survival to apoptotic. Thus, stimulation of a single class of receptors, β2-ARs, elicits concurrent apoptotic and survival signals in cardiac myocytes. The survival effect appears to predominate and is mediated by the Gi-Gβγ-PI3K-Akt signaling pathway.