Cardiovascular Research Advance Access first published online on January 15, 2009
This version [Accepted Manuscript] published online on January 20, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp014
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Cardiac Regulation by Phosphoinositide 3-kinases and PTEN
1 Division of Cardiology, Department of Medicine, University of Alberta, Canada
2 Mazankowski Alberta Heart Institute, University of Alberta, Canada
3 IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Austria
Address for Correspondence: Gavin Y. Oudit, MD, PhD, FRCPC Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute University of Alberta, Edmonton Alberta, T6G 2B7, Canada Phone: 780-407-8569; Fax: 780-407- 6452 gavin.oudit{at}ualberta.ca
The diverse effects mediated by PI3K/PTEN signaling in the heart clearly support an important biological and pathophysiological role for this signaling cascade. Phosphoinositide 3-kinases (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 (RTK)/cytokine receptor activation (class IA) or G-protein-coupled receptors (GPCR) (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
, β and 
) and class IB (PI3K
) PI3Ks mediate distinct phenotypes in the heart under negative control by the 3'-lipid phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome ten), which dephosphorylates PtdIns(3,4,5)P3 to generate PtdIns(4,5)P2. PI3K, PI3K 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 signaling pathways are involved in a wide variety of diseases including myocardial hypertrophy and contractility, heart failure and preconditioning. In this review, we discuss the signaling pathways mediated by PI3K class I isoforms and PTEN and their roles in cardiac structure and function.
Time for primary review: 37 Days
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