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Dynamic regulation of phosphoinositide 3-kinase-gamma activity and beta-adrenergic receptor trafficking in end-stage human heart failure.

Publication ,  Journal Article
Perrino, C; Schroder, JN; Lima, B; Villamizar, N; Nienaber, JJ; Milano, CA; Naga Prasad, SV
Published in: Circulation
November 27, 2007

BACKGROUND: Downregulation of beta-adrenergic receptors (betaARs) under conditions of heart failure requires receptor targeting of phosphoinositide 3-kinase (PI3K)-gamma and redistribution of betaARs into endosomal compartments. Because support with a left ventricular assist device (LVAD) results in significant improvement of cardiac function in humans, we investigated the effects of mechanical unloading on regulation of PI3Kgamma activity and intracellular distribution of betaARs. Additionally, we tested whether displacement of PI3Kgamma from activated betaARs would restore agonist responsiveness in failing human cardiomyocytes. METHODS AND RESULTS: To test the role of PI3K on betaAR endocytosis in failing human hearts, we assayed for PI3K activity in human left ventricular samples before and after mechanical unloading (LVAD). Before LVAD, failing human hearts displayed a marked increase in betaAR kinase 1 (betaARK1)-associated PI3K activity that was attributed exclusively to enhanced activity of the PI3Kgamma isoform. Increased betaARK1-coupled PI3K activity in the failing hearts was associated with downregulation of betaARs from the plasma membrane and enhanced sequestration into early and late endosomes compared with unmatched nonfailing controls. Importantly, LVAD support reversed PI3Kgamma activation, normalized the levels of agonist-responsive betaARs at the plasma membrane, and depleted the betaARs from the endosomal compartments without changing the total number of receptors (sum of plasma membrane and early and late endosome receptors). To test whether the competitive displacement of PI3K from the betaAR complex restored receptor responsiveness, we overexpressed the phosphoinositide kinase domain of PI3K (which disrupts betaARK1/PI3K interaction) in primary cultures of failing human cardiomyocytes. Adenoviral-mediated phosphoinositide kinase overexpression significantly increased basal contractility and rapidly reconstituted responsiveness to beta-agonist. CONCLUSIONS: These results suggest a novel paradigm in which human betaARs undergo a process of intracellular sequestration that is dynamically reversed after LVAD support. Importantly, mechanical unloading leads to complete reversal in PI3Kgamma and betaARK1-associated PI3K activation. Furthermore, displacement of active PI3K from betaARK1 restores betaAR responsiveness in failing myocytes.

Duke Scholars

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

November 27, 2007

Volume

116

Issue

22

Start / End Page

2571 / 2579

Location

United States

Related Subject Headings

  • Ventricular Function, Left
  • Receptors, Adrenergic, beta
  • Protein Transport
  • Phosphatidylinositol 3-Kinases
  • Muscle Cells
  • Middle Aged
  • Male
  • Isoenzymes
  • In Vitro Techniques
  • Humans
 

Citation

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Perrino, C., Schroder, J. N., Lima, B., Villamizar, N., Nienaber, J. J., Milano, C. A., & Naga Prasad, S. V. (2007). Dynamic regulation of phosphoinositide 3-kinase-gamma activity and beta-adrenergic receptor trafficking in end-stage human heart failure. Circulation, 116(22), 2571–2579. https://doi.org/10.1161/CIRCULATIONAHA.107.706515
Perrino, Cinzia, Jacob N. Schroder, Brian Lima, Nestor Villamizar, Jeffrey J. Nienaber, Carmelo A. Milano, and Sathyamangla V. Naga Prasad. “Dynamic regulation of phosphoinositide 3-kinase-gamma activity and beta-adrenergic receptor trafficking in end-stage human heart failure.Circulation 116, no. 22 (November 27, 2007): 2571–79. https://doi.org/10.1161/CIRCULATIONAHA.107.706515.
Perrino C, Schroder JN, Lima B, Villamizar N, Nienaber JJ, Milano CA, et al. Dynamic regulation of phosphoinositide 3-kinase-gamma activity and beta-adrenergic receptor trafficking in end-stage human heart failure. Circulation. 2007 Nov 27;116(22):2571–9.
Perrino, Cinzia, et al. “Dynamic regulation of phosphoinositide 3-kinase-gamma activity and beta-adrenergic receptor trafficking in end-stage human heart failure.Circulation, vol. 116, no. 22, Nov. 2007, pp. 2571–79. Pubmed, doi:10.1161/CIRCULATIONAHA.107.706515.
Perrino C, Schroder JN, Lima B, Villamizar N, Nienaber JJ, Milano CA, Naga Prasad SV. Dynamic regulation of phosphoinositide 3-kinase-gamma activity and beta-adrenergic receptor trafficking in end-stage human heart failure. Circulation. 2007 Nov 27;116(22):2571–2579.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

November 27, 2007

Volume

116

Issue

22

Start / End Page

2571 / 2579

Location

United States

Related Subject Headings

  • Ventricular Function, Left
  • Receptors, Adrenergic, beta
  • Protein Transport
  • Phosphatidylinositol 3-Kinases
  • Muscle Cells
  • Middle Aged
  • Male
  • Isoenzymes
  • In Vitro Techniques
  • Humans