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

• Wei-Zhong Zhu

  Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; Department of Surgery and Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710; and Howard Hughes Medical Institute, Stanford University Medical Center, Stanford, CA 94305

• Ming Zheng

  Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; Department of Surgery and Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710; and Howard Hughes Medical Institute, Stanford University Medical Center, Stanford, CA 94305

• Walter J. Koch

  Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; Department of Surgery and Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710; and Howard Hughes Medical Institute, Stanford University Medical Center, Stanford, CA 94305

• Robert J. Lefkowitz

  Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; Department of Surgery and Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710; and Howard Hughes Medical Institute, Stanford University Medical Center, Stanford, CA 94305

• Brian K. Kobilka

  Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; Department of Surgery and Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710; and Howard Hughes Medical Institute, Stanford University Medical Center, Stanford, CA 94305

• Rui-Ping Xiao

  Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; Department of Surgery and Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710; and Howard Hughes Medical Institute, Stanford University Medical Center, Stanford, CA 94305

抄録

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.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 98 (4), 1607-1612, 2001-02-13

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1363107369651552128
• NII論文ID: 80012204640
• DOI: 10.1073/pnas.98.4.1607
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.98.4.1607
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