This Article Full Text Full Text (PDF) All Versions of this Article: 108/17/2147    most recent 01.CIR.0000091403.62293.2Bv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oudit, G. Y. Articles by Penninger, J. M. Search for Related Content PubMed PubMed Citation Articles by Oudit, G. Y. Articles by Penninger, J. M. Pubmed/NCBI databases OMIM Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Failure

(Circulation. 2003;108:2147.)
© 2003 American Heart Association, Inc.

Basic Science Reports

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; 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.

Correspondence to J.M. Penninger, University Health Network, University of Toronto, 620 University Ave, Toronto, Ontario M5G 2C1, Canada. E-mail jpenning{at}uhnres.utoronto.ca

Received December 12, 2002; de novo received April 28, 2003; revision received June 3, 2003; accepted June 17, 2003.

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 ß-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 ß-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 ß-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. ß₁- and ß₂-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 ß-adrenergic receptors after chronic ß-adrenergic stimulation.

Conclusions— Our data show that PI3K is critical for the induction of hypertrophy, fibrosis, and cardiac dysfunction function in response to ß-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

This article has been cited by other articles:

				G. Y. Oudit and J. M. Penninger Cardiac regulation by phosphoinositide 3-kinases and PTEN Cardiovasc Res, May 1, 2009; 82(2): 250 - 260. [Abstract] [Full Text] [PDF]

				C.-C. Yeh, D. Malhotra, H. Li, S. Nicholas, R. Tu, and M. J. Mann Surgical ventricular reconstruction in mice: Elucidating potential targets for combined molecular/surgical intervention J. Thorac. Cardiovasc. Surg., April 1, 2009; 137(4): 942 - 949. [Abstract] [Full Text] [PDF]

				Y. G. Wang, X. Ji, M. Pabbidi, A. M. Samarel, and S. L. Lipsius Laminin acts via focal adhesion kinase/phosphatidylinositol-3' kinase/protein kinase B to down-regulate {beta}1-adrenergic receptor signalling in cat atrial myocytes J. Physiol., February 1, 2009; 587(3): 541 - 550. [Abstract] [Full Text] [PDF]

				G. Y. Oudit, Z. Kassiri, J. Zhou, Q. C. Liu, P. P. Liu, P. H. Backx, F. Dawood, M. A. Crackower, J. W. Scholey, and J. M. Penninger Loss of PTEN attenuates the development of pathological hypertrophy and heart failure in response to biomechanical stress Cardiovasc Res, June 1, 2008; 78(3): 505 - 514. [Abstract] [Full Text] [PDF]

				B.-G. Kerfant, D. Zhao, I. Lorenzen-Schmidt, L. S. Wilson, S. Cai, S. R. W. Chen, D. H. Maurice, and P. H. Backx PI3K{gamma} Is Required for PDE4, not PDE3, Activity in Subcellular Microdomains Containing the Sarcoplasmic Reticular Calcium ATPase in Cardiomyocytes Circ. Res., August 17, 2007; 101(4): 400 - 408. [Abstract] [Full Text] [PDF]

				N. Yano, V. Ianus, T. C. Zhao, A. Tseng, J. F. Padbury, and Y.-T. Tseng A novel signaling pathway for beta-adrenergic receptor-mediated activation of phosphoinositide 3-kinase in H9c2 cardiomyocytes Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H385 - H393. [Abstract] [Full Text] [PDF]

				L.-X. Li, P. E. MacDonald, D. S. Ahn, G. Y. Oudit, P. H. Backx, and P. L. Brubaker Role of Phosphatidylinositol 3-Kinase{gamma} in the {beta}-Cell: Interactions with Glucagon-Like Peptide-1 Endocrinology, July 1, 2006; 147(7): 3318 - 3325. [Abstract] [Full Text] [PDF]

				B.-G. Kerfant, D. Gidrewicz, H. Sun, G. Y. Oudit, J. M. Penninger, and P. H. Backx Cardiac Sarcoplasmic Reticulum Calcium Release and Load Are Enhanced by Subcellular cAMP Elevations in PI3K{gamma}-Deficient Mice Circ. Res., May 27, 2005; 96(10): 1079 - 1086. [Abstract] [Full Text] [PDF]

				R. Ricci, U. Eriksson, G. Y. Oudit, R. Eferl, A. Akhmedov, I. Sumara, G. Sumara, Z. Kassiri, J.-P. David, L. Bakiri, et al. Distinct functions of junD in cardiac hypertrophy and heart failure Genes & Dev., January 15, 2005; 19(2): 208 - 213. [Abstract] [Full Text] [PDF]

				P. E. MacDonald, J. W. Joseph, D. Yau, J. Diao, Z. Asghar, F. Dai, G. Y. Oudit, M. M. Patel, P. H. Backx, and M. B. Wheeler Impaired Glucose-Stimulated Insulin Secretion, Enhanced Intraperitoneal Insulin Tolerance, and Increased {beta}-Cell Mass in Mice Lacking the p110{gamma} Isoform of Phosphoinositide 3-Kinase Endocrinology, September 1, 2004; 145(9): 4078 - 4083. [Abstract] [Full Text] [PDF]

				M. Asahi, K. Otsu, H. Nakayama, S. Hikoso, T. Takeda, A. O. Gramolini, M. G. Trivieri, G. Y. Oudit, T. Morita, Y. Kusakari, et al. Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) activity and impairs cardiac function in mice PNAS, June 22, 2004; 101(25): 9199 - 9204. [Abstract] [Full Text] [PDF]