Skip to main content
Journal cover image

Targeted inhibition of beta-adrenergic receptor kinase-1-associated phosphoinositide-3 kinase activity preserves beta-adrenergic receptor signaling and prolongs survival in heart failure induced by calsequestrin overexpression.

Publication ,  Journal Article
Perrino, C; Naga Prasad, SV; Patel, M; Wolf, MJ; Rockman, HA
Published in: J Am Coll Cardiol
June 7, 2005

OBJECTIVES: Desensitization and down-regulation of beta-adrenergic receptors (betaARs) are prominent features of heart failure largely mediated by increased levels of betaAR kinase-1 (betaARK1). BACKGROUND: beta-adrenergic receptor kinase 1 interacts with phosphoinositide-3 kinase (PI3K), and upon agonist stimulation, the betaARK1/PI3K complex is recruited to agonist-stimulated betaARs. Here we tested the hypothesis that in vivo selective inhibition of betaARK1-associated PI3K activity would preserve betaAR signaling and, therefore, improve cardiac function and survival in experimental heart failure. METHODS: We used a murine model of heart failure induced by calsequestrin (CSQ) cardiac-specific overexpression; CSQ mice were crossed with mice overexpressing in the heart a catalytically inactive PI3Kgamma (PI3Kgamma(inact)) to competitively displace endogenous PI3K from betaARK1. RESULTS: Catalytically inactive PI3KgammaPI3K overexpression in CSQ mice inhibited betaARK1-associated PI3K activity, normalized betaAR levels, and preserved betaAR responsiveness to isoproterenol (ISO). Restoration of betaAR signaling via PI3Kgamma(inact) overexpression resulted in marked improvement of cardiac function and a significant prolongation of survival. Importantly, the effects of PI3Kgamma(inact) overexpression were restricted to betaAR signaling, because cellular PI3K signaling was unaltered, as shown by the similar activation of multiple downstream signaling pathways in both CSQ and CSQ/PI3Kgamma(inact) mice. CONCLUSIONS: These data in the CSQ model of cardiac dysfunction indicate that membrane-targeted PI3K activity plays a detrimental role in heart failure, and its inhibition represents a novel therapeutic approach to ameliorate cardiac dysfunction and improve survival.

Duke Scholars

Published In

J Am Coll Cardiol

DOI

ISSN

0735-1097

Publication Date

June 7, 2005

Volume

45

Issue

11

Start / End Page

1862 / 1870

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Phosphatidylinositol 3-Kinases
  • Mice, Transgenic
  • Mice, Inbred Strains
  • Mice
  • Immunoproliferative Disorders
  • Immunoblotting
  • Down-Regulation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Perrino, C., Naga Prasad, S. V., Patel, M., Wolf, M. J., & Rockman, H. A. (2005). Targeted inhibition of beta-adrenergic receptor kinase-1-associated phosphoinositide-3 kinase activity preserves beta-adrenergic receptor signaling and prolongs survival in heart failure induced by calsequestrin overexpression. J Am Coll Cardiol, 45(11), 1862–1870. https://doi.org/10.1016/j.jacc.2005.02.062
Perrino, Cinzia, Sathyamangla V. Naga Prasad, Mrinali Patel, Matthew J. Wolf, and Howard A. Rockman. “Targeted inhibition of beta-adrenergic receptor kinase-1-associated phosphoinositide-3 kinase activity preserves beta-adrenergic receptor signaling and prolongs survival in heart failure induced by calsequestrin overexpression.J Am Coll Cardiol 45, no. 11 (June 7, 2005): 1862–70. https://doi.org/10.1016/j.jacc.2005.02.062.
Journal cover image

Published In

J Am Coll Cardiol

DOI

ISSN

0735-1097

Publication Date

June 7, 2005

Volume

45

Issue

11

Start / End Page

1862 / 1870

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Phosphatidylinositol 3-Kinases
  • Mice, Transgenic
  • Mice, Inbred Strains
  • Mice
  • Immunoproliferative Disorders
  • Immunoblotting
  • Down-Regulation