Phosphoinositide 3-kinase gamma-deficient mice are protected from isoproterenol-induced heart failure.
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.
Oudit
Gavin Y
GY
Department of Physiology, University Health Network, University of Toronto, 620 University Ave, Toronto, Ontario M5G 2C1, Canada.
Crackower
Michael A
MA
Eriksson
Urs
U
Sarao
Renu
R
Kozieradzki
Ivona
I
Sasaki
Takehiko
T
Irie-Sasaki
Junko
J
Gidrewicz
Dominica
D
Rybin
Vitalyi O
VO
Wada
Teiji
T
Steinberg
Susan F
SF
Backx
Peter H
PH
Penninger
Josef M
JM
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
D000318:Adrenergic beta-Agonists; D019869:Phosphatidylinositol 3-Kinases; D007545:Isoproterenol