title: Phosphoinositide 3-kinase gamma-deficient mice are protected from isoproterenol-induced heart failure.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Physiology, University Health Network, University of Toronto, 620 University Ave, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.forename: Michael A
authors.initials: MA
authors.lastname: Crackower
authors.forename: Urs
authors.initials: U
authors.lastname: Eriksson
authors.forename: Renu
authors.initials: R
authors.lastname: Sarao
authors.forename: Ivona
authors.initials: I
authors.lastname: Kozieradzki
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Junko
authors.initials: J
authors.lastname: Irie-Sasaki
authors.forename: Dominica
authors.initials: D
authors.lastname: Gidrewicz
authors.forename: Vitalyi O
authors.initials: VO
authors.lastname: Rybin
authors.forename: Teiji
authors.initials: T
authors.lastname: Wada
authors.forename: Susan F
authors.initials: SF
authors.lastname: Steinberg
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D000318:Adrenergic beta-Agonists; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D020134:Catalytic Domain / Q000235:genetics; D004195:Disease Models, Animal; D005355:Fibrosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D007545:Isoproterenol; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000318:Adrenergic beta-Agonists; D019869:Phosphatidylinositol 3-Kinases; D007545:Isoproterenol