Document Detail

Phosphoinositide 3-kinase gamma-deficient mice are protected from isoproterenol-induced heart failure.
MedLine Citation:
PMID:  12963636     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: We have recently shown that genetic inactivation of phosphoinositide 3-kinase gamma (PI3Kgamma), the isoform linked to G-protein-coupled receptors, results in increased cardiac contractility with no effect on basal cell size. Signaling via the G-protein-coupled beta-adrenergic receptors has been implicated in cardiac hypertrophy and heart failure, suggesting that PI3Kgamma might play a role in the pathogenesis of heart disease. METHODS AND RESULTS: To determine the role for PI3Kgamma in hypertrophy induced by G-protein-coupled receptors and cardiomyopathy, we infused isoproterenol, a beta-adrenergic receptor agonist, into PI3Kgamma-deficient mice. Compared with controls, isoproterenol infusion in PI3Kgamma-deficient mice resulted in an attenuated cardiac hypertrophic response and markedly reduced interstitial fibrosis. Intriguingly, chronic beta-adrenergic receptor stimulation triggered impaired heart functions in wild-type mice, whereas PI3Kgamma-deficient mice retained their increased heart function and did not develop heart failure. The lack of PI3Kgamma attenuated the activation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 signaling pathways in cardiac myocytes in response to isoproterenol. beta1- and beta2-adrenergic receptor densities were decreased by similar amounts in PI3Kgamma-deficient and control mice, suggesting that PI3Kgamma isoform plays no role in the downregulation of beta-adrenergic receptors after chronic beta-adrenergic stimulation. CONCLUSIONS: Our data show that PI3Kgamma is critical for the induction of hypertrophy, fibrosis, and cardiac dysfunction function in response to beta-adrenergic receptor stimulation in vivo. Thus, PI3Kgamma may represent a novel therapeutic target for the treatment of decreased cardiac function in heart failure.
Gavin Y Oudit; Michael A Crackower; Urs Eriksson; Renu Sarao; Ivona Kozieradzki; Takehiko Sasaki; Junko Irie-Sasaki; Dominica Gidrewicz; Vitalyi O Rybin; Teiji Wada; Susan F Steinberg; Peter H Backx; Josef M Penninger
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2003-09-08
Journal Detail:
Title:  Circulation     Volume:  108     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2003 Oct 
Date Detail:
Created Date:  2003-10-28     Completed Date:  2003-11-24     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2147-52     Citation Subset:  AIM; IM    
Department of Physiology, University Health Network, University of Toronto, 620 University Ave, Toronto, Ontario M5G 2C1, Canada.
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / deficiency*,  genetics
Adrenergic beta-Agonists
Cardiomegaly / chemically induced,  enzymology,  prevention & control
Catalytic Domain / genetics
Disease Models, Animal
Fibrosis / genetics,  pathology,  prevention & control
Heart / drug effects
Heart Failure / chemically induced,  enzymology*,  pathology,  prevention & control*
Mice, Knockout
Myocardium / enzymology,  pathology
Signal Transduction / drug effects,  genetics
Reg. No./Substance:
0/Adrenergic beta-Agonists; 7683-59-2/Isoproterenol; EC 3-Kinase

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