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Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure.

Publication ,  Journal Article
Adams, JW; Sakata, Y; Davis, MG; Sah, VP; Wang, Y; Liggett, SB; Chien, KR; Brown, JH; Dorn, GW
Published in: Proc Natl Acad Sci U S A
August 18, 1998

Receptor-mediated Gq signaling promotes hypertrophic growth of cultured neonatal rat cardiac myocytes and is postulated to transduce in vivo cardiac pressure overload hypertrophy. Although initially compensatory, hypertrophy can proceed by unknown mechanisms to cardiac failure. We used adenoviral infection and transgenic overexpression of the alpha subunit of Gq to autonomously activate Gq signaling in cardiomyocytes. In cultured cardiac myocytes, overexpression of wild-type Galphaq resulted in hypertrophic growth. Strikingly, expression of a constitutively activated mutant of Galphaq, which further increased Gq signaling, produced initial hypertrophy, which rapidly progressed to apoptotic cardiomyocyte death. This paradigm was recapitulated during pregnancy in Galphaq overexpressing mice and in transgenic mice expressing high levels of wild-type Galphaq. The consequence of cardiomyocyte apoptosis was a transition from compensated hypertrophy to a rapidly progressive and lethal cardiomyopathy. Progression from hypertrophy to apoptosis in vitro and in vivo was coincident with activation of p38 and Jun kinases. These data suggest a mechanism in which moderate levels of Gq signaling stimulate cardiac hypertrophy whereas high level Gq activation results in cardiomyocyte apoptosis. The identification of a single biochemical stimulus regulating cardiomyocyte growth and death suggests a plausible mechanism for the progression of compensated hypertrophy to decompensated heart failure.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

August 18, 1998

Volume

95

Issue

17

Start / End Page

10140 / 10145

Location

United States

Related Subject Headings

  • Signal Transduction
  • Rats
  • Pregnancy
  • Myocardium
  • Mitogen-Activated Protein Kinases
  • Mice, Transgenic
  • Mice
  • JNK Mitogen-Activated Protein Kinases
  • Humans
  • Heart Failure
 

Citation

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Adams, J. W., Sakata, Y., Davis, M. G., Sah, V. P., Wang, Y., Liggett, S. B., … Dorn, G. W. (1998). Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad Sci U S A, 95(17), 10140–10145. https://doi.org/10.1073/pnas.95.17.10140
Adams, J. W., Y. Sakata, M. G. Davis, V. P. Sah, Y. Wang, S. B. Liggett, K. R. Chien, J. H. Brown, and G. W. Dorn. “Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure.Proc Natl Acad Sci U S A 95, no. 17 (August 18, 1998): 10140–45. https://doi.org/10.1073/pnas.95.17.10140.
Adams JW, Sakata Y, Davis MG, Sah VP, Wang Y, Liggett SB, et al. Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10140–5.
Adams, J. W., et al. “Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure.Proc Natl Acad Sci U S A, vol. 95, no. 17, Aug. 1998, pp. 10140–45. Pubmed, doi:10.1073/pnas.95.17.10140.
Adams JW, Sakata Y, Davis MG, Sah VP, Wang Y, Liggett SB, Chien KR, Brown JH, Dorn GW. Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10140–10145.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

August 18, 1998

Volume

95

Issue

17

Start / End Page

10140 / 10145

Location

United States

Related Subject Headings

  • Signal Transduction
  • Rats
  • Pregnancy
  • Myocardium
  • Mitogen-Activated Protein Kinases
  • Mice, Transgenic
  • Mice
  • JNK Mitogen-Activated Protein Kinases
  • Humans
  • Heart Failure