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Restoration of beta-adrenergic receptor signaling and contractile function in heart failure by disruption of the betaARK1/phosphoinositide 3-kinase complex.

Publication ,  Journal Article
Perrino, C; Naga Prasad, SV; Schroder, JN; Hata, JA; Milano, C; Rockman, HA
Published in: Circulation
May 24, 2005

BACKGROUND: Desensitization and downregulation of myocardial beta-adrenergic receptors (betaARs) are initiated by the increase in betaAR kinase 1 (betaARK1) levels. By interacting with betaARK1 through the phosphoinositide kinase (PIK) domain, phosphoinositide 3-kinase (PI3K) is targeted to agonist-stimulated betaARs, where it regulates endocytosis. We tested the hypothesis that inhibition of receptor-targeted PI3K activity would alter receptor trafficking and ameliorate betaAR signaling, ultimately improving contractility of failing cardiomyocytes. METHODS AND RESULTS: To competitively displace PI3K from betaARK1, we generated mice with cardiac-specific overexpression of the PIK domain. Seven-day isoproterenol administration in wild-type mice induced desensitization of betaARs and their redistribution from the plasma membrane to early and late endosomes. In contrast, transgenic PIK overexpression prevented the redistribution of betaARs away from the plasma membrane and preserved their responsiveness to agonist. We further tested whether PIK overexpression could normalize already established betaAR abnormalities and ameliorate contractile dysfunction in a large animal model of heart failure induced by rapid ventricular pacing in pigs. Failing porcine hearts showed increased betaARK1-associated PI3K activity and marked desensitization and redistribution of betaARs to endosomal compartments. Importantly, adenoviral gene transfer of the PIK domain in failing pig myocytes resulted in reduced receptor-localized PI3K activity and restored to nearly normal agonist-stimulated cardiomyocyte contractility. CONCLUSIONS: These data indicate that the heart failure state is associated with a maladaptive redistribution of betaARs away from the plasma membrane that can be counteracted through a strategy that targets the betaARK1/PI3K complex.

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Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

May 24, 2005

Volume

111

Issue

20

Start / End Page

2579 / 2587

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Swine
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Protein Transport
  • Protein Binding
  • Phosphatidylinositol 3-Kinases
  • Myocardial Contraction
  • Mice, Transgenic
  • Mice
 

Citation

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Perrino, C., Naga Prasad, S. V., Schroder, J. N., Hata, J. A., Milano, C., & Rockman, H. A. (2005). Restoration of beta-adrenergic receptor signaling and contractile function in heart failure by disruption of the betaARK1/phosphoinositide 3-kinase complex. Circulation, 111(20), 2579–2587. https://doi.org/10.1161/CIRCULATIONAHA.104.508796
Perrino, Cinzia, Sathyamangla V. Naga Prasad, Jacob N. Schroder, Jonathan A. Hata, Carmelo Milano, and Howard A. Rockman. “Restoration of beta-adrenergic receptor signaling and contractile function in heart failure by disruption of the betaARK1/phosphoinositide 3-kinase complex.Circulation 111, no. 20 (May 24, 2005): 2579–87. https://doi.org/10.1161/CIRCULATIONAHA.104.508796.
Perrino C, Naga Prasad SV, Schroder JN, Hata JA, Milano C, Rockman HA. Restoration of beta-adrenergic receptor signaling and contractile function in heart failure by disruption of the betaARK1/phosphoinositide 3-kinase complex. Circulation. 2005 May 24;111(20):2579–87.
Perrino, Cinzia, et al. “Restoration of beta-adrenergic receptor signaling and contractile function in heart failure by disruption of the betaARK1/phosphoinositide 3-kinase complex.Circulation, vol. 111, no. 20, May 2005, pp. 2579–87. Pubmed, doi:10.1161/CIRCULATIONAHA.104.508796.
Perrino C, Naga Prasad SV, Schroder JN, Hata JA, Milano C, Rockman HA. Restoration of beta-adrenergic receptor signaling and contractile function in heart failure by disruption of the betaARK1/phosphoinositide 3-kinase complex. Circulation. 2005 May 24;111(20):2579–2587.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

May 24, 2005

Volume

111

Issue

20

Start / End Page

2579 / 2587

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Swine
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Protein Transport
  • Protein Binding
  • Phosphatidylinositol 3-Kinases
  • Myocardial Contraction
  • Mice, Transgenic
  • Mice