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Cardiovascular Research Advance Access originally published online on January 15, 2009
Cardiovascular Research 2009 82(2):250-260; doi:10.1093/cvr/cvp014
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Cardiac regulation by phosphoinositide 3-kinases and PTEN

Gavin Y. Oudit1,* and Josef M. Penninger2

1 Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada T6G 2B7
2 IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria

* Corresponding author. Tel: +1 780 407 8569; fax: +1 780 407 6452. E-mail address: gavin.oudit{at}ualberta.ca

The diverse effects mediated by PI3K/PTEN (phosphoinositide 3-kinase/phosphatase and tensin homologue deleted on chromosome 10) signalling in the heart clearly support an important biological and pathophysiological role for this signalling cascade. PI3Ks are a family of evolutionarily conserved lipid kinases that mediate many cellular responses to physiological and pathophysiological stimuli. Class I PI3K can be activated by either receptor tyrosine kinase/cytokine receptor activation (class IA) or G-protein-coupled receptors (class IB), leading to the generation of phosphatidyl inositol (3,4,5)P3 and recruitment and activation of Akt/protein kinase B, 3'-phosphoinositide-dependent kinase-1 (PDK1), or monomeric G-proteins, and phosphorylation of a wide range of downstream targets including glycogen synthase kinase 3β (GSK3β), mTOR (mammalian target of rapamycin), p70S6 kinase, endothelial nitric oxide synthase, and several anti-apoptotic effectors. Class IA (PI3K{alpha}, β, and {delta}) and class IB (PI3K{gamma}) PI3Ks mediate distinct phenotypes in the heart under negative control by the 3'-lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4,5)P3 to generate PtdIns(4,5)P2. PI3K{alpha}, PI3K{gamma}, and PTEN are expressed in cardiomyocytes, fibroblasts, endothelial cells, and vascular smooth muscle cells, where they modulate cell survival, hypertrophy, contractility, metabolism, and mechanotransduction. The PI3K/PTEN signalling pathways are involved in a wide variety of diseases including myocardial hypertrophy and contractility, heart failure, and preconditioning. In this review, we discuss the signalling pathways mediated by PI3K class I isoforms and PTEN and their roles in cardiac structure and function.

KEYWORDS P13 kinase; Akt; Signalling; Hypertrophy; Heart failure

Time for primary review: 37 days


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