Published Online
on September 8, 2003

A more recent version of this article appeared on October 28, 2003

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Submitted on December 12, 2002
Revised on June 3, 2003
Accepted on June 17, 2003

Phosphoinositide 3-Kinase -Deficient Mice Are Protected From Isoproterenol-Induced Heart Failure

Gavin Y. Oudit MSc, MD, Michael A. Crackower PhD, Urs Eriksson MD, Renu Sarao MSc, Ivona Kozieradzki MSc, Takehiko Sasaki MD, Junko Irie-Sasaki MD, Dominica Gidrewicz MSc, Vitalyi O. Rybin PhD, Teiji Wada MD, Susan F. Steinberg MD, Peter H. Backx DVM, PhD, and Josef M. Penninger MD^*

From the Departments of Physiology and Medicine (G.Y.O., D.G., P.H.B.) and Medical Biophysics and Immunology (U.E., R.S., I.K., T.W., J.M.P.), University Health Network , University of Toronto, Ontario, Canada; Department of Functional Genomics (M.A.C.), Amgen Inc, Thousand Oaks, Calif; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (U.E., R.S., I.K., T.W., J.M.P.), Vienna, Austria; Department of Pharmacology (T.S., J.-I.S.), The Tokyo Metropolitan Institute of Medical Science, Japan; PRESTO (T.S., J.-I.S.), Japan Science and Technology Corporation (T.S., J.-I.S.), Tokyo, Japan; and Department of Pharmacology (V.O.R., S.F.S.), College of Physicians and Surgeons, Columbia University, New York, NY.

^* To whom correspondence should be addressed. E-mail: jpenning{at}uhnres.utoronto.ca.

Background--We have recently shown that genetic inactivation of phosphoinositide 3-kinase (PI3K), 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 -adrenergic receptors has been implicated in cardiac hypertrophy and heart failure, suggesting that PI3K might play a role in the pathogenesis of heart disease.

Methods and Results--To determine the role for PI3K in hypertrophy induced by G-protein-coupled receptors and cardiomyopathy, we infused isoproterenol, a -adrenergic receptor agonist, into PI3K-deficient mice. Compared with controls, isoproterenol infusion in PI3K-deficient mice resulted in an attenuated cardiac hypertrophic response and markedly reduced interstitial fibrosis. Intriguingly, chronic -adrenergic receptor stimulation triggered impaired heart functions in wild-type mice, whereas PI3K-deficient mice retained their increased heart function and did not develop heart failure. The lack of PI3K attenuated the activation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 signaling pathways in cardiac myocytes in response to isoproterenol. ₁- and ₂-adrenergic receptor densities were decreased by similar amounts in PI3K-deficient and control mice, suggesting that PI3K isoform plays no role in the downregulation of -adrenergic receptors after chronic -adrenergic stimulation.

Conclusions--Our data show that PI3K is critical for the induction of hypertrophy, fibrosis, and cardiac dysfunction function in response to -adrenergic receptor stimulation in vivo. Thus, PI3K may represent a novel therapeutic target for the treatment of decreased cardiac function in heart failure.

Key words: heart failure • signal transduction • hypertrophy

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