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

Abstract

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.

PKA phosphorylates histone deacetylase 5 and prevents its nuclear export, leading to the inhibition of gene transcription and cardiomyocyte hypertrophy

“…The MAPK pathway has been implicated in cardiac hypertrophy induced by β2-AR stimulation (44,45). PI3Kγ, which is activated through Gi-associated Gβγ, plays an essential role in isoproterenol-induced cardiac hypertrophy and heart failure (46,47). Although the net effect of isoproterenol through multiple signaling pathways is enhanced cardiac hypertrophy, our studies suggest a negative pathway for cardiomyocyte hypertrophy in isoproterenol signaling that may provide a means for manipulating isoproterenol/β-AR responses in heart.…”

A novel signaling pathway for β-adrenergic receptor-mediated activation of phosphoinositide 3-kinase in H9c2 cardiomyocytes

“…␤-AR stimulation in vitro leads to recruitment of PI3K␥ to B-ARK, which results in receptor internalization (30). Disruption of these interactions in vivo is beneficial because it 1) prevents ␤-AR downregulation induced by chronic agonist administration; and 2) preserves cardiac function under chronic pressure overload (32). Animals with disruption of PI3K␥ gene are protected from chronic ␤-AR stimulation-induced heart failure (33).…”

“…6A, lanes 9 and 10). The basal cardiac PI3K␥ activity is usually low in the heart without chronic ␤-AR stimulation (30,32, and personal communication, Drs. Sathyamangla Naga Prasad and Howard A. Rockman).…”

Designing Heart Performance by Gene Transfer

“…Transient PIK expression decreased PI3K localization with ␤-ARs in sarcoma cells, and viral-mediated gene transfer of PIK into myocytes from failing pig hearts restored the isoproterenol-mediated enhancement of peak shortening and contraction and relaxation rates toward the nonfailing phenotype (683). The loss of ␤-ARs, increased norepinephrine (NE) levels, and/or chronic ␤-AR activation that result from heart failure are ultimately maladaptive (640,683). Future studies may focus on gene therapy utilizing modified proteins associated with the ␤-AR cycling pathway, such as ␤-arrestin (477) and PDE4 (375,488), which serve as important proteins in scaffolding and/or desensitization of ␤ 2 -ARs.…”