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

Citation
Wz. Zhu et al., Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes, P NAS US, 98(4), 2001, pp. 1607-1612
Citations number
44
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN journal
0027-8424 → ACNP
Volume
98
Issue
4
Year of publication
2001
Pages
1607 - 1612
Database
ISI
SICI code
0027-8424(20010213)98:4<1607:DMOCSA>2.0.ZU;2-2
Abstract
The goal of this study was to determine whether beta (1)-adrenergic recepto r (AR) and beta (2)-AR differ in regulating cardiomyocyte survival and apop tosis 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, wher eas cardiac beta (1)-AR couples only to G(s). To avoid complicated crosstal k between beta -AR subtypes, we expressed beta (1)-AR or beta (2)-AR indivi dually in adult beta (1)/beta (2)-AR double knockout mouse cardiac myocytes by using adenoviral gene transfer. Stimulation of beta (1)-AR, but not bet a (2)-AR, markedly induced myocyte apoptosis, as indicated by increased ter minal deoxynucleotidyltransferase-mediated UTP end labeling or Hoechst stai ning positive cells and DNA fragmentation. In contrast, beta (2)-AR (but no t beta (1)-AR) stimulation elevated the activity of Akt, a powerful surviva l 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 p eptide inhibitor of G(beta gamma)), or LY294002, respectively. This indicat es that beta (2)-AR activates Akt via a G(i)-G(beta gamma)-PI3K pathway. Mo re importantly, inhibition of the G(i)-G beta gamma -PI3K-Akt pathway conve rts 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 predo minate and is mediated by the G(i)-G(beta gamma)-PI3K-Akt signaling pathway .