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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Nienaber, JJ; Tachibana, H; Naga Prasad, SV; Esposito, G; Wu, D; Mao, L; Rockman, HA

Published Date

  • October 1, 2003

Published In

Volume / Issue

  • 112 / 7

Start / End Page

  • 1067 - 1079

PubMed ID

  • 14523044

Pubmed Central ID

  • 14523044

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/JCI200318213

Language

  • eng