Inhibition of receptor-localized PI3K preserves cardiac β-adrenergic receptor function and ameliorates pressure overload heart failure
Jeffrey J. Nienaber, … , Lan Mao, Howard A. Rockman
Jeffrey J. Nienaber, … , Lan Mao, Howard A. Rockman
Published October 1, 2003
Citation Information: J Clin Invest. 2003;112(7):1067-1079. https://doi.org/10.1172/JCI18213.
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Inhibition of receptor-localized PI3K preserves cardiac β-adrenergic receptor function and ameliorates pressure overload heart failure

Abstract

β-Adrenergic receptor (βAR) downregulation and desensitization are hallmarks of the failing heart. However, whether abnormalities in βAR function are mechanistically linked to the cause of heart failure is not known. We hypothesized that downregulation of cardiac βARs can be prevented through inhibition of PI3K activity within the receptor complex, because PI3K is necessary for βAR internalization. Here we show that in genetically modified mice, disrupting the recruitment of PI3K to agonist-activated βARs in vivo prevents receptor downregulation in response to chronic catecholamine administration and ameliorates the development of heart failure with pressure overload. Disruption of PI3K/βAR colocalization is required to preserve βAR signaling, since deletion of a single PI3K isoform (PI3Kγ knockout) is insufficient to prevent the recruitment of other PI3K isoforms and subsequent βAR downregulation with catecholamine stress. These data demonstrate a specific role for receptor-localized PI3K in the regulation of βAR turnover and show that abnormalities in βAR 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 βAR-localized PI3K activity represents a novel therapeutic approach to restore normal βAR signaling and preserve cardiac function in the pressure overloaded failing heart.

Authors

Jeffrey J. Nienaber, Hideo Tachibana, Sathyamangla V. Naga Prasad, Giovanni Esposito, Dianqing Wu, Lan Mao, Howard A. Rockman

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Figure 5

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Cardiac-specific overexpression of PI3Kγinact does not alter downstream ...
Cardiac-specific overexpression of PI3Kγinact does not alter downstream PI3K signaling. (a) JNK, ERK, p38, and p38β MAPK activities from 1 mg left ventricular myocardial extracts of WT and PI3Kγinact mice under unstimulated conditions. Myocardial extracts (100 μg) from WT and PI3Kγinact mice immunoblotted for pPKB and pGSK. White bars, WT; black bars, PI3Kγinact. *P < 0.01 PI3Kγinact versus WT. (b) Myocardial extracts from WT and PI3Kγ-KO mice immunoblotted for pPKB and pGSK. (c and d) pPKB, pGSK, and phospho-ERK (pERK) immunoblots from 100 μg of myocardial extract of WT and PI3Kγinact mice following 7 days of ISO treatment (c) and upon insulin stimulation (d). (e) Hypertrophic response to pressure overload induced by TAC measured as a ratio of left ventricular weight (LVW/BW) is plotted against the systolic pressure gradient produced by transverse aortic constriction for each WT (open circles: n = 15) and PI3Kγinact (closed circles: n = 19) mouse. Mean pressure gradient between the groups was similar, WT 83.3 ± 6.1 and PI3Kγinact 77.0 ± 3.6 mmHg. JNK, c-Jun NH2-terminal kinase; ERK, extracellular signal-regulated kinase; PKB, protein kinase B; GSK, glycogen synthase kinase B; MBP, myelin basic protein.