Review ArticleThe role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease
Section snippets
Phosphatidylinositol metabolism
Phosphatidylinositols (PtdIns) are phospholipids that are comprised of a phosphoglyceride esterified to the hydroxyl group of inositol (Fig. 1A). The inositol ring can be phosphorylated and dephosphorylated at various positions by an array of lipid kinases and phosphatases (Fig. 1B) [1], [2], [3]. Phosphatidylinositol-4-phosphate (i.e. PtdIns(4)P) and phosphatidylinositol-4,5-phosphate (i.e. PtdIns(4,5)P2) are the major phosphorylated PtdIns present at basal conditions which are reported to
Structure and function of PI3Ks
PI3Ks are divided into three classes according to their substrate specificity, mode of activation and molecular structure [1], [3], [12], [13] (Table 1). Our review will focus on class IA and IB PI3Ks which are heterodimeric enzymes composed of a regulatory adapter (accessory) subunit coupled to a tightly bound catalytic subunit [3], [12], [13]. Class IA catalytic subunits include p110α, β and δ while the class IB catalytic subunit is p110γ (Table 1) [3], [13]. The class IA PI3K adapter
PTEN—3′-lipid phosphatase and a negative regulator of PI3Ks
Phosphoinositide phosphatases are divided into three different families. The CX5R family contains PTEN and myotubularin (MTM) which are 3′- and 4′-phosphatases while SHIP-1 and -2 are 5′-phosphatases [3]. PTEN is also known as “mutated in multiple advanced cancers” (MMAC1) as well as the TGFβ-regulated and epithelial cell-enriched phosphatase (TEP1), and was first identified as tumor-suppressor gene localized on chromosome 10q23 [3], [19], [62]. Somatic mutations in PTEN are often found in many
Molecular targets of PI3K/PTEN signaling
PI3K/PTEN are the primary regulators of PtdIns(3,4,5)P3 and PtdIns(3,4)P2 (and PtdIns(4,5)P2) which mediate selective targeting and activation of many downstream effectors by binding to PH, FYVE (named after four proteins containing this domain: Fab1, YOTB, Vac1 and EEA1), phox homology (PX), epsin N-terminal homology (ENTH), SH2 and C2 domains [3], [100], [101], [102]. The PH domain is of particular importance and consist of about 120 amino acids residues having a unique three-dimensional
Cell survival and apoptosis
PI3K activation enhances cell survival and antagonizes apoptosis via Akt/PKB in many cell types including cardiomyocytes [148], [149], [150], cardiac fibroblast [151], VSMCs [152] and endothelial cells [126], [150]. Consistent with Akt/PKB multi-compartment signaling [123], [124], anti-apoptotic action of Akt/PKB involve both cytoplasmic and nuclear compartments via modulation of bad, caspase-3, caspase-3, Forkhead transcription factors and IκB kinase [121], [122], [153], [154]. Growth factors
Isoform-specific signaling by class I PI3K: interaction with PTEN
Cell signaling involves spatial and temporal integration of multiple signaling pathways [32], [47], [188], [244] as illustrated in the heart with intracellular Ca2+ [188], [245], cAMP [185], [186], [188] and NO signaling [201]. Recent studies have established that PI3K/PTEN signaling is also spatially and functionally restricted in many cell types including cardiomyocytes [36], [197], fibroblasts [32], [246], neutrophils [247], neurons [122] and breast cancer cells [248] Under basal conditions,
Role of PI3K in preconditioning
Ischemic preconditioning (IPC) refers to a phenomenon where brief periods of mild ischemia can protect the heart from subsequent ischemia. Acute IPC lasts approximately 2 h while a second window of protection (i.e. delayed IPC) develops 24 h later and lasts approximately 3 d [269], [270]. Preconditioning involves the release of several autacoids that trigger protection by activating various receptors, cell signaling cascades and effectors [269], [271], [272], [273]. In acute IPC there is
Role of PI3K and PTEN in heart failure
PI3K/Akt and several downstream pathways are activated in heart disease including myocardial ischemia/reperfusion [276], [277], [281], [282], diabetic-associated cardiomyopathy [170], [283], adriamycin-induced cardiomyopathy [159], [284], chronic β-AR stimulation [40], [178], pressure-overload-induced hypertrophy [156], [172], [176] and in advanced human heart failure [243], [285]. However, class IA and IB PI3K isoforms appear to have distinct roles in the pathogenesis of heart disease. Animal
PI3K and PTEN in vascular function and diseases
Both class IA (PI3Kα and β) and IB (PI3Kγ) isoforms, lipid phosphatases (PTEN and SHIP2) [23], [39], [41], [42], [86], [214], [314] and several downstream targets of PI3K including Akt1/PKBα, Akt2/PKBβ, Akt3/PKBγ, GSK3α/β and mTOR/p70S6K1 have been shown to be expressed in VSMCs [39], [125], [145], [315]. PI3K/Akt and PTEN are involved in both cytosolic and nuclear signaling in endothelial and VSMCs where they regulate vascular homeostasis and angiogenesis, as well as VSMC growth and
Pharmacologic inhibitors of PI3K
The pharmacologic inhibitors of PI3Ks have been useful tools in advancing our understanding of the biology of PI3Ks. WM and LY294002, the two most widely used PI3K inhibitors, are low-molecular-weight and cell-permeable compounds that are structurally and mechanistically distinct antagonists of all three classes of PI3Ks. WM was originally isolated from Penicillium wortmannii and irreversibly inactivates the PI3Ks by covalent modification of the catalytic subunit, p110 [3], [333], [334].
Future perspectives
The diverse effects mediated by PI3K/PTEN signaling in the heart and vasculature clearly support an important biologic and pathophysiologic role for this signaling cascade. This has provided great hope for future therapies for hypertension, vascular restenosis, ischemia/reperfusion injury and congestive heart failure. The distinct roles of class IA and IB PI3K isoforms suggest that therapeutic manipulation of PI3K/PTEN system may require isoform specific targeting. However, many aspects of
Acknowledgements
We acknowledge the financial support from the Canadian Institute for Health Research (P.H.B.) and Heart and Stroke Foundation of Ontario (P.H.B.). G.Y.O. is a recipient of a Post-Doctoral Fellowship from the Canadian Institute for Health Research and the Heart and Stroke Foundation of Canada and is a Fellow of the TACTICS program. P.H.B. is a Career Investigator of the Heart and Stroke Foundation of Ontario.
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