Journal
CARDIOVASCULAR RESEARCH
Volume 82, Issue 2, Pages 250-260Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvp014
Keywords
P13 kinase; Akt; Signalling; Hypertrophy; Heart failure
Categories
Funding
- Canadian Institute for Health Research [86602]
- Heart and Stroke Foundation of Ontario (G.Y.O.)
- Alberta Heritage Foundation for Medical Research (G.Y.O.)
- EuGeneHeart (EU 6th Framework programmes)
- Genome Austria (GEN-AU)
- IMBA (J.M.P.)
- Alberta Heritage Medical Research Foundation
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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 I(A)) or G-protein-coupled receptors (class I(B)), leading to the generation of phosphatidyl inositol (3,4,5)P(3) 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 3 beta (GSK3 beta), mTOR (mammalian target of rapamycin), p70S6 kinase, endothelial nitric oxide synthase, and several anti-apoptotic effectors. Class I(A) (PI3K alpha, beta, and delta) and class I(B) (PI3K gamma) PI3Ks mediate distinct phenotypes in the heart under negative control by the 3'-lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4,5)P(3) to generate PtdIns(4,5)P(2). 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.
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