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

Abstract

HomeCirculationVol. 102, No. 21Dual Modulation of Cell Survival and Cell Death by β2-Adrenergic Gi and Gs Signaling in Adult Mouse Cardiac Myocytes Free AccessOtherPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessOtherPDF/EPUBDual Modulation of Cell Survival and Cell Death by β2-Adrenergic Gi and Gs Signaling in Adult Mouse Cardiac Myocytes Wei-Zhong Zhu, Ming Zheng, Brian Kobilka and Rui-Ping Xiao Wei-Zhong ZhuWei-Zhong Zhu Laboratory of Cardiovascular Science, GRC, NIA, NIH, Baltimore, N4D 21224; Search for more papers by this author , Ming ZhengMing Zheng Laboratory of Cardiovascular Science, GRC, NIA, NIH, Baltimore, N4D 21224; Search for more papers by this author , Brian KobilkaBrian Kobilka Laboratory of Cardiovascular Science, GRC, NIA, NIH, Baltimore, N4D 21224; Search for more papers by this author and Rui-Ping XiaoRui-Ping Xiao Laboratory of Cardiovascular Science, GRC, NIA, NIH, Baltimore, N4D 21224; Search for more papers by this author Originally published21 Nov 2000https://doi.org/10.1161/01.CIR.102.21.2672-kCirculation. 2000;102:2672Cardiac β2-AR activates both Gs and Gi proteins whereas β1-AR couples only to Gs. The goal of this study is to determine whether β1-AR and β2-AR differ in regulating cardiomyocyte survival and apoptosis, if so, to explore underlying mechanisms. To avoid complicated crosstalks between β-AR subtypes, we express β1-AR or β2-AR individually in the null background of β1 β2 double knockout mouse cardiomyocytes using adult mouse myocyte culture and adenoviral gene transfer techniques. Stimulation of β1-AR, but not β2-AR. markedly induces myocyte apoptosis, as indicated by increased TUNEL or Hoechst staining positive cells and DNA fragmentation. Inhibition Gi signaling with pertussis toxin converts β2-AR to β1-AR in terms of its apoptotic effect, suggesting that Gi is essential for β2-AR-mediated survival effect. To explore the downstream signaling events of β2-AR-coupled Gi, we first examined the possible involvement of p38 MAPK, since recent studies propose that p38 MAPK underlies Gi-dependent anti-apoptotic effects. We found that although stimulation of either β-AR subtype increases p38 MAPK activity, this effect is insensitive to PTX, excluding a role of p38 MAPK in β2-AR-mediated cell-survival. In contrast, β2-AR (but not β1-AR) elevates the activity of Akt, a powerful survival signal; this effect is fully abolished by inhibiting Gi with pertussis toxin, scavenging Gβγ with βARK-ct, or blocking PI3K with LY294002, indicating that β2-AR activates Akt via Giβγ-PI3K pathway. Most importantly, inhibition of the Giβγ-PI3K-Akt pathway converts β2-AR signaling from survival to apoptotic. Thus, β2-AR, unlike β1-AR, activates concurrent apoptotic and survival signals in cardiomyocytes, and the survival effect is mediated by the Giβγ-PI3K-Akt pathway. The strikingly different effects of β-AR subtypes on cardiac cell survival and apoptosis may have important pathophysiological and therapeutic implications in chronic heart failure. Previous Back to top Next FiguresReferencesRelatedDetails November 21, 2000Vol 102, Issue 21 Advertisement Article InformationMetrics Copyright © 2000 by American Heart Associationhttps://doi.org/10.1161/01.CIR.102.21.2672-k Originally publishedNovember 21, 2000 PDF download Advertisement