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Inhibition of receptor-localized PI3K preserves cardiac beta-adrenergic receptor function and ameliorates pressure overload heart failure.

Publication ,  Journal Article
Nienaber, JJ; Tachibana, H; Naga Prasad, SV; Esposito, G; Wu, D; Mao, L; Rockman, HA
Published in: J Clin Invest
October 2003

beta-Adrenergic receptor (betaAR) downregulation and desensitization are hallmarks of the failing heart. However, whether abnormalities in betaAR function are mechanistically linked to the cause of heart failure is not known. We hypothesized that downregulation of cardiac betaARs can be prevented through inhibition of PI3K activity within the receptor complex, because PI3K is necessary for betaAR internalization. Here we show that in genetically modified mice, disrupting the recruitment of PI3K to agonist-activated betaARs in vivo prevents receptor downregulation in response to chronic catecholamine administration and ameliorates the development of heart failure with pressure overload. Disruption of PI3K/betaAR colocalization is required to preserve betaAR signaling, since deletion of a single PI3K isoform (PI3Kgamma knockout) is insufficient to prevent the recruitment of other PI3K isoforms and subsequent betaAR downregulation with catecholamine stress. These data demonstrate a specific role for receptor-localized PI3K in the regulation of betaAR turnover and show that abnormalities in betaAR function are associated with the development of heart failure. Thus, a strategy that blocks the membrane translocation of PI3K and leads to the inhibition of betaAR-localized PI3K activity represents a novel therapeutic approach to restore normal betaAR signaling and preserve cardiac function in the pressure overloaded failing heart.

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Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

October 2003

Volume

112

Issue

7

Start / End Page

1067 / 1079

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Receptors, Adrenergic, beta
  • Protein Transport
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphatidylinositol 3-Kinases
  • Mice, Knockout
  • Mice
  • Isoproterenol
  • Immunology
  • Heart Failure
 

Citation

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ICMJE
MLA
NLM
Nienaber, J. J., Tachibana, H., Naga Prasad, S. V., Esposito, G., Wu, D., Mao, L., & Rockman, H. A. (2003). Inhibition of receptor-localized PI3K preserves cardiac beta-adrenergic receptor function and ameliorates pressure overload heart failure. J Clin Invest, 112(7), 1067–1079. https://doi.org/10.1172/JCI18213
Nienaber, Jeffrey J., Hideo Tachibana, Sathyamangla V. Naga Prasad, Giovanni Esposito, Dianqing Wu, Lan Mao, and Howard A. Rockman. “Inhibition of receptor-localized PI3K preserves cardiac beta-adrenergic receptor function and ameliorates pressure overload heart failure.J Clin Invest 112, no. 7 (October 2003): 1067–79. https://doi.org/10.1172/JCI18213.
Nienaber JJ, Tachibana H, Naga Prasad SV, Esposito G, Wu D, Mao L, et al. Inhibition of receptor-localized PI3K preserves cardiac beta-adrenergic receptor function and ameliorates pressure overload heart failure. J Clin Invest. 2003 Oct;112(7):1067–79.
Nienaber, Jeffrey J., et al. “Inhibition of receptor-localized PI3K preserves cardiac beta-adrenergic receptor function and ameliorates pressure overload heart failure.J Clin Invest, vol. 112, no. 7, Oct. 2003, pp. 1067–79. Pubmed, doi:10.1172/JCI18213.
Nienaber JJ, Tachibana H, Naga Prasad SV, Esposito G, Wu D, Mao L, Rockman HA. Inhibition of receptor-localized PI3K preserves cardiac beta-adrenergic receptor function and ameliorates pressure overload heart failure. J Clin Invest. 2003 Oct;112(7):1067–1079.

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

October 2003

Volume

112

Issue

7

Start / End Page

1067 / 1079

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Receptors, Adrenergic, beta
  • Protein Transport
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphatidylinositol 3-Kinases
  • Mice, Knockout
  • Mice
  • Isoproterenol
  • Immunology
  • Heart Failure