[Frontiers in Bioscience 14, 2221-2229, January 1, 2009]
Role of phosphoinositide 3-kinases in regulating cardiac function
Lynette Pretorius1,2, Kate L. Owen1,3, Julie R. McMullen1
1
TABLE OF CONTENTS
1. ABSTRACT
Phosphoinositide 3-kinases (PI3Ks) are important signaling proteins in the heart. Class IA PI3Ks (p110a , b ) are critical regulators of physiological heart growth and cell survival, and are generally considered to be beneficial for heart function. In contrast, activation of class IB PI3K(p110g ) is detrimental for heart function, reducing cardiac contractility. This may have implications for the treatment of heart disease and failure. In vitro, ex vivo and in vivo studies have contributed to our understanding of PI3K signaling in the heart. This review summarizes class I PI3K signaling in the regulation of cardiac function, with a particular focus on the role of different PI3K isoforms in settings of heart disease.
2. INTRODUCTION
Understanding the role of key signaling proteins on cardiac function is of importance as it aids our understanding of the pathophysiological mechanisms involved in heart failure, a condition in which cardiac function is compromised. Heart failure has reached near-epidemic proportions in much of the Western world, affecting approximately 1-2% of the population (1-3). Phosphoinositide 3-kinases (PI3Ks) have been identified as important regulators of cardiomyocyte growth, survival, and contractility. This review will summarize the roles of different PI3K isoforms in regulating cardiac function, both in the healthy heart and in settings of disease.
3. PHOSPHOINOSITIDE 3-KINASE (PI3K)
PI3Ks are important signaling proteins in numerous cell types. PI3Ks catalyze the phosphorylation of lipids in the cell membrane, leading to the generation of second messengers such as phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3). There are three major classes of PI3Ks (classes I-III). These are determined based on amino acid sequence, homology of the lipid-kinase domains, and specificity for substrate binding (4, 5). Class I PI3Ks consist of a 110kDa catalytic subunit (p110) complexed with a regulatory subunit, and can be divided into two subclasses: IA and IB. Class IA PI3Ks (p110a , p110b and p110d ) associate with the regulatory proteins p85a , p85b and p55g (as well as spliced variants of p85a ), while p110g (the only class IB PI3K identified to date) is regulated by p101 (6). p110a , b and g are expressed in the heart (7) and vasculature (8-10), while p110d is found predominantly in leukocytes (see (6)) and will not be addressed in this review. p85a is the most abundant isoform of the class IA regulatory subunits expressed in the heart (see (11)).
Class IA PI3Ks are activated by receptor tyrosine kinases, such as platelet-derived growth factor (PDGF) receptor, epidermal growth factor (EGF) receptor, and insulin-like growth factor 1 (IGF1) receptor (see (12)) (Figure 1). Binding of growth factors to these receptors results in autophosphorylation of specific tyrosine residues in the intracellular domains, providing a docking site for p85 (13). Subsequent activation of the p110 catalytic subunit results in phosphorylation of lipid substrates in the cell membrane, namely phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). The product of this reaction, PtdIns(3,4,5)P3, acts as a second messenger, recruiting proteins to the cell surface where they can be modified by other enzymes (12). Class IB PI3Ks are activated by binding to the Gb g subunits of heterotrimeric G proteins following stimulation of G protein-coupled receptors (14, 15) (Figure 1).
4. ROLE OF PI3K SIGNALING IN THE HEART: EVIDENCE FROM IN VITRO AND EX VIVO STUDIES
In vitro and ex vivo studies using PI3K inhibitors (e.g. Wortmannin, LY294002) have implicated PI3K in a diverse range of cellular processes. For example, administration of IGF1 reduced myocardial injury and improved cardiac function in rat hearts subjected to ischemia-reperfusion injury (16). Wortmannin reduced the beneficial effects of IGF1 in this model, suggesting that PI3K plays an important role in the regulation of contractile function. In another study, ischemia-reperfusion induced activation of Akt (a downstream target of PI3K), and this was blocked by Wortmannin, implicating PI3K in stress responses (17). Inhibition of PI3K by LY294002 significantly increased cell contractility and transient calcium levels in isolated rat cardiomyocytes following stimulation by a b 2AR agonist (18). Another study demonstrated that IGF1 protected rat fibroblasts from apoptosis induced by UV radiation (19). This protection was completely inhibited by the addition of Wortmannin, implicating PI3K in cell survival (19).
In vitro and ex vivo studies are limited, however, as the PI3K inhibitors available are not isoform-specific. Additionally, LY294002 has been shown to specifically inhibit slowly inactivating K+ currents leading to increased Ca2+ release and myocyte contractility (20), consequently limiting the usefulness of this inhibitor to examine the role of PI3K in regulating cardiac function. Thus, the specific functions of different PI3K isoforms are still being elucidated. Of particular interest is the role of class I PI3Ks in the heart, as components of class I PI3K signaling pathways are emerging as potential therapeutic targets for the treatment of cardiovascular disease and heart failure (21).
5. IN VIVO STUDIES INVESTIGATING PI3K SIGNALING IN THE HEALTHY HEART
Transgenic and knockout mouse models have provided a powerful approach for understanding the specific roles of different PI3K isoforms in the heart. In the following section, we have focused on PI3K(p110a ) and PI3K(p110g ), as these isoforms have been identified as important regulators of heart structure and function.
5.1. PI3K(p110a ) mediates physiological cardiomyocyte hypertrophy
Studies in cardiac-specific PI3K transgenic mice have demonstrated that the p110a isoform of PI3K is critical for developmental, IGF1-induced and exercise-induced heart growth (physiological cardiac hypertrophy) (22-24). Unlike pathological cardiac hypertrophy (heart growth due to disease), physiological hypertrophy is characterized by normal cardiac structure and function, and does not lead to decompensation. Mice expressing a cardiac-specific constitutively active (ca) form of PI3K(p110a ) displayed a 6.5 fold increase in PI3K(p110a ) activity, which was associated with a 20% increase in heart size compared with control mice (non-transgenics) (24). Mice expressing a dominant negative (dn) PI3K mutant displayed a 77% decrease in PI3K activity, and had 20% smaller hearts compared with non-transgenics (23, 24). Importantly, caPI3K and dnPI3K mice showed no signs of cardiomyopathy (such as fibrosis) and had normal cardiac function and lifespan under basal conditions (23, 24). dnPI3K mice showed a blunted response to exercise (a stimulus that induces physiological heart growth), but not to pressure overload (a pathological stimulus that leads to maladaptive heart growth, cell death and fibrosis), suggesting that PI3K(p110a ) is critical for physiological, but not pathological, induced cardiac growth (23). These studies were later confirmed using a knockout approach. Deletion of class IA PI3Ks from cardiac myocytes in mice led to a reduction in heart size that was similar in magnitude to that observed in dnPI3K mice (25). Knockout mice also showed a blunted cardiac hypertrophic response to exercise training (25).
IGF1 is an upstream agonist for class IA PI3K (i.e. p110a , b ) activation in the heart (22, 26). Transgenic mice overexpressing IGF1 receptors in the heart exhibited a 40% increase in heart size and no signs of histopathology, as well as enhanced left ventricular systolic function (approximately 15% increase) at three months of age (22). Heart growth due to the overexpression of IGF1 receptors was completely blocked by crossing IGF1 receptor transgenic mice with dnPI3K transgenic mice, suggesting that IGF1-induced hypertrophy is PI3K(p110a )-dependent (22) (Figure 1).
PI3K(p110a ) signaling appears to promote cardiomyocyte hypertrophy via activation of Akt (also known as protein kinase B). Akt is a known downstream effector of PI3K, and is activated by phosphoinositide-dependent kinase 1 (PDK1) upon recruitment to the cell surface by PtdIns(3,4,5)P3 (27). Akt phosphorylation was elevated in hearts of caPI3K mice and decreased in hearts of dnPI3K mice, consistent with the differences in cardiac PI3K activity in these mice (24). Akt1 has been identified as an essential mediator of physiological cardiac hypertrophy, as Akt1 knockout mice were resistant to increases in heart size induced by chronic exercise training (28).
5.2. PI3K(p110g ) negatively regulates cardiac contractility
The p110g isoform of PI3K appears to be a negative regulator of cardiac contractility, as knockout mice lacking PI3K(p110g ) displayed enhanced contractile function (7) (Figure 1). Loss of PI3K(p110g ) in these mice had no effect on heart size under basal conditions (7), however PI3K(p110g ) appears to contribute to cardiac hypertrophy in settings of pathological stress (15, 29) (see section 6.4).
PI3K(p110g ) mediates cardiac contractility by regulating the activity of phosphodiesterases (PDEs; enzymes that degrade cyclic AMP, cAMP), as loss of PI3K(p110g ) in mouse myocardium eliminated PDE4 activity with beneficial consequences for cardiomyocyte contractility (30). Production of cAMP following b -adrenergic receptor stimulation results in activation of cAMP-dependent protein kinase (PKA), an enzyme that regulates intracellular Ca2+ levels by phosphorylating proteins involved in excitation-contraction coupling (such as L-type Ca2+ channels, ryanodine receptors, and phospholamban (PLN), a protein that regulates sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) activity) (31). Binding of PI3K(p110g ) to PDEs results in degradation of cAMP, reducing contractility.
PI3K(p110g ) also regulates heart rate via negative modulation of the spontaneous firing rate of sinoatrial node myocytes (32), possibly by affecting sarcoplasmic Ca2+ cycling rates (33, 34).
6. PI3K SIGNALING IN THE FAILING HEART
Heart failure occurs when the heart loses its ability to provide sufficient perfusion to meet the metabolic demands of the body, and can result from a variety of conditions that impair and overload the heart (such as hypertension, cardiomyopathy, and myocardial infarction) (35, 36). Numerous structural events contribute to the depressed function of the failing heart. These include pathological cardiac hypertrophy, which is associated with distinct changes in gene expression; cell death (via apoptosis and necrosis), which reduces the number of cardiomyocytes available for contraction; and fibrosis, which leads to mechanical stiffness. The following section will outline the role of PI3K in preventing or mediating these events.
6.1. PI3K(p110a ) attenuates pathological cardiac hypertrophy and associated changes in gene expression
Pathological cardiac hypertrophy is a key event in the progression from a cardiac insult to heart failure. Pathological hypertrophy is initially considered an adaptive response to pressure or volume overload on the heart, however prolonged exposure to a pathological stimulus can cause the heart to decompensate (37). Pathological hypertrophy is associated with distinct changes in gene expression, increased interstitial fibrosis, cell death, and depressed cardiac function (21, 38-40).
Constitutive activation of PI3K(p110a ) in transgenic mice (i.e. caPI3K) attenuated pathological cardiac hypertrophy induced by pressure overload (aortic-banding), a pathological stimulus that mimics hypertension in the ventricle (41). In contrast, mice expressing a dominant negative PI3K mutant (i.e. dnPI3K) exhibited a massive (approximately 80%) increase in heart weight, increased interstitial fibrosis, and severe lung congestion in response to pressure overload (41). Thus, in response to a physiological stimulus a decrease in PI3K(p110a ) activity blunts hypertrophic growth (see section 5.1); whereas in response to a pathological stimulus a decrease in PI3K(p110a ) activity exaggerates pathological heart growth. Hearts of aortic-banded dnPI3K transgenic mice also showed significantly more dilation and decompensated more rapidly than non-transgenics. These data suggest that PI3K(p110a ) is critical for maintaining cardiac structure and function in a setting of pressure overload, via the suppression of pathological cardiac hypertrophy, ventricular dilation, and the regulation of fibrosis (Figure 1). Of note, disruption of other receptor tyrosine kinases (e.g. ErbB2 receptors) also impairs growth and promotes cardiac dilation (42, 43).
Differential regulation of gene expression during pathological hypertrophy is a likely contributory factor for depressed cardiac function (44, 45). Aortic-banding studies have shown that pathological hypertrophy is associated with re-expression of fetal genes, including atrial and B-type natriuretic peptides (ANP and BNP respectively), b -myosin heavy chain (b -MHC) and a -skeletal actin (23, 46, 47). Severe/advanced pathological hypertrophy is accompanied by a decrease in SERCA2a expression (48-50). SERCA2a plays an important role in excitation-contraction coupling, promoting relaxation by pumping Ca2+ ions into the sarcoplasmic reticulum. Downregulation of SERCA2a is detrimental for heart function (45, 51), and transgenic mice with reduced SERCA2a activity developed heart failure more rapidly than non-transgenics in response to pressure overload (52).
PI3K(p110a ) may protect the heart in a setting of pressure overload by attenuating changes in gene expression associated with pathological cardiac hypertrophy. As noted earlier, PI3K(p110a ) is critical for exercise-induced heart growth. Swimming training reversed molecular abnormalities associated with pathological cardiac hypertrophy in hypertensive rats (53), and increased PI3K(p110a ) activity in caPI3K mice attenuated the drop in SERCA2a expression due to pressure overload (41). IGF1-PI3K signaling might also improve cardiac structure and function by upregulating genes involved in cardiomyocyte contraction, such as a -skeletal actin, tropomyosin 3g , and actin capping protein a (22). Overexpression of a -skeletal actin or tropomyosin 3g in the mouse heart enhanced contractility (54, 55), while actin capping proteins are important for filament length regulation, as well as sarcomere organization and muscle function (56-58). As previously mentioned, a -skeletal actin is re-expressed during pathological cardiac hypertrophy; this may be an attempt to preserve function in a setting of cardiac dysfunction.
6.2. Class IA PI3Ks promote cell survival
Cell death (i.e. apoptosis and necrosis) is a key feature of heart failure (59-61), contributing to the depressed function of the failing heart by reducing the number of cardiomyocytes available for contraction. Numerous studies have implicated PI3K-Akt signaling in cell survival (e.g. (62, 63)), however mechanisms in the heart are still being elucidated. Administration or transgenic overexpression of IGF1 reduced the death of cardiomyocytes in settings of disease (64, 65), suggesting that the class IA PI3Ks (which lie downstream of IGF1 receptors) are the isoforms responsible for PI3K-dependent cell survival in the heart.
In non-cardiac cells, Akt promotes cell survival via inhibition of pro-apoptotic factors such as procaspase-9 and Bad (66, 67). In vitro studies have demonstrated that PI3K-dependent activation of Akt in neonatal cardiomyocytes resulted in Bad phosphorylation and prolonged cell survival (68, 69). However, expression of Bad is significantly downregulated during the neonatal period and is very low in the adult heart (70), suggesting that inhibition of Bad via phosphorylation by Akt is not a major contributor to cell survival in the adult heart. Caspase-9 activity was elevated in neonatal cardiomyocytes subjected to hypoxia, but decreased when the cells were pre-treated with epoxyeicosatrienoic acid, a fatty acid that induces activation of the PI3K-Akt pathway (69). Activation of PI3K-Akt was also associated with an increase in X-linked inhibitor of apoptosis protein (XIAP) expression (69). XIAP is an anti-apoptotic protein that prevents cell death by binding to caspases (71). Thus, in the neonatal heart, PI3K-Akt signaling appears to promote cell survival via activation of XIAP and inhibition of Bad and caspase-9. Further investigation is required to identify the downstream substrates responsible for the anti-apoptotic effects of PI3K signaling in the adult heart.
6.3. PI3K(p110a ) reduces cardiac fibrosis
A fine network of collagen fibres surrounds cardiac myocytes under normal conditions. This collagen matrix is important for structural support and myofibrillar alignment when the heart contracts. However, a build-up of collagen in the interstitial space between cardiomyocytes (i.e. increased interstitial fibrosis) is detrimental for heart function, disrupting the cardiac conduction system (72, 73) and causing mechanical stiffness (74).
PI3K(p110a ) appears to be a negative regulator of fibrosis, as hearts of dnPI3K mice contained greater interstitial fibrosis compared with non-transgenics in response to pressure overload, while hearts of caPI3K mice contained less fibrosis (41). Microarray analysis suggests that PI3K-dependent regulation of fibrosis during pressure overload occurs at the level of transcription, as dnPI3K mice expressed higher levels of fibrotic genes (such as procollagen, fibronectin and fibrillin), while caPI3K mice expressed lower levels compared with non-transgenics (41).
6.4. The role of PI3K(p110g ) in settings of pathological stress
In general, PI3K(p110g ) activation appears to have a detrimental effect in the heart. PI3K(p110g ) knockout mice were protected from heart failure induced by chronic activation of b -adrenergic receptors (b -ARs), displaying less fibrosis, a significantly smaller hypertrophic response and better heart function than controls (29). PI3K(p110g ) might contribute to cardiac dysfunction via its effects on b -AR internalization (Figure 1). Downregulation and desensitization of b -ARs is a key feature of end-stage heart failure, and is detrimental for heart function (75, 76). Downregulation of b -AR on the plasma membrane is achieved via sequestration of b -ARs in endosomes. This process is dependent on the binding of p110g to b -AR kinase 1 (b -ARK1) (77). Expression of a catalytically inactive p110g mutant or disruption of the interaction between b -ARK1 and p110g restored b -AR signaling and contractile function in transgenic mice subjected to chronic b -AR stimulation (78, 79). The beneficial effects of loss of PI3K(p110g ) may also be related to the maintenance of Ca2+ cycling at the level of the sarcoplasmic reticulum (SR) via altered PDE activity. Loss of p110g causes a decrease in PDE activity resulting in increased intracellular cAMP levels, enhanced phosphorylation of PLN and SERCA2a activity. This leads to an increased SR Ca2+ load and enhanced calcium release from the SR (80). Consequently, inhibition of PI3K(p110g ) may be a therapeutic strategy in the treatment of heart failure. Of note, however, the role PI3K(p110g ) in the diseased heart is complex and appears to vary depending on the nature of the pathological stress. PI3K(p110g ) knockout mice displayed an accelerated progression to dilated cardiomyopathy in response to pressure-overload (80, 81).
7. CONCLUSION
PI3K(p110a ) and PI3K(p110g ) play very different roles in the heart. PI3K(p110a ) is critical for physiological cardiac hypertrophy, and activation of PI3K(p110a ) is important for maintaining cardiac structure and function in pathological settings. In contrast, activation of PI3K(p110g ) is generally detrimental for heart function, reducing heart contractility via the internalization of b -ARs and inhibition of SERCA2a activity (Figure 1). Further investigation of the signaling pathways mediated by these isoforms of PI3K might lead to the development of new treatments for cardiovascular disease and failure.
8. ACKNOWLEDGEMENTS
LP and KLO contributed equally to this review. We acknowledge funding support from the National Health and Medical Research Council (NHMRC) of Australia and the National Heart Foundation of Australia. LP and KLO are supported by Australian Postgraduate Awards and Baker Foundation Postgraduate Awards. JRM is supported by a Career Development Award co-funded by the NHMRC and National Heart Foundation of Australia.
9. REFERENCES
1. AIHW: Heart, stroke and vascular diseases - Australian facts 2004. A report from the Heart Foundation and the Australian Institute of Health and Welfare. Cardiovascular Disease Series, 22, 1-152 (2004)
2. Thom, T., N. Haase, W. Rosamond, V. J. Howard, J. Rumsfeld, T. Manolio, Z. J. Zheng, K. Flegal, C. O'Donnell, S. Kittner, D. Lloyd-Jones, D. C. Goff, Jr., Y. Hong, R. Adams, G. Friday, K. Furie, P. Gorelick, B. Kissela, J. Marler, J. Meigs, V. Roger, S. Sidney, P. Sorlie, J. Steinberger, S. Wasserthiel-Smoller, M. Wilson, P. Wolf, C. American Heart Association Statistics & S. Stroke Statistics: Heart disease and stroke statistics--2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 113, 14 (2006)
doi:10.1161/CIRCULATIONAHA.105.171600
3. CDC: Health, United States, with chartbook on trends in the health of Americans. Centers for Disease Control and Prevention & National Center for Health Statistics(2006)
4. Fruman, D. A., R. E. Meyers & L. C. Cantley: Phosphoinositide kinases. Annual Review of Biochemistry, 67, 481-507 (1998)
doi:10.1146/annurev.biochem.67.1.481
5. Vanhaesebroeck, B., S. J. Leevers, G. Panayotou & M. D. Waterfield: Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends in Biochemical Sciences, 22, 267-72 (1997)
doi:10.1016/S0968-0004(97)01061-X
6. Vanhaesebroeck, B. & M. D. Waterfield: Signaling by distinct classes of phosphoinositide 3-kinases. Experimental Cell Research, 253, 239-54 (1999)
doi:10.1006/excr.1999.4701
7. Crackower, M. A., G. Y. Oudit, I. Kozieradzki, R. Sarao, H. Sun, T. Sasaki, E. Hirsch, A. Suzuki, T. Shioi, J. Irie-Sasaki, R. Sah, H. Y. Cheng, V. O. Rybin, G. Lembo, L. Fratta, A. J. Oliveira-dos-Santos, J. L. Benovic, C. R. Kahn, S. Izumo, S. F. Steinberg, M. P. Wymann, P. H. Backx & J. M. Penninger: Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell, 110, 737-49 (2002)
doi:10.1016/S0092-8674(02)00969-8
8. Northcott, C. A., M. N. Poy, S. M. Najjar & S. W. Watts: Phosphoinositide 3-kinase mediates enhanced spontaneous and agonist-induced contraction in aorta of deoxycorticosterone acetate-salt hypertensive rats. Circulation Research, 91, 360-9 (2002)
doi:10.1161/01.RES.0000030861.13850.F1
9. Bacqueville, D., P. Deleris, C. Mendre, M. T. Pieraggi, H. Chap, G. Guillon, B. Perret & M. Breton-Douillon: Characterization of a G protein-activated phosphoinositide 3-kinase in vascular smooth muscle cell nuclei. Journal of Biological Chemistry, 276, 22170-6 (2001)
doi:10.1074/jbc.M011572200
10. Quignard, J. F., J. Mironneau, V. Carricaburu, B. Fournier, A. Babich, B. Nurnberg, C. Mironneau & N. Macrez: Phosphoinositide 3-kinase gamma mediates angiotensin II-induced stimulation of L-type calcium channels in vascular myocytes. Journal of Biological Chemistry, 276, 32545-51 (2001)
doi:10.1074/jbc.M102582200
11. Oudit, G. Y., H. Sun, B. G. Kerfant, M. A. Crackower, J. M. Penninger & P. H. Backx: The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. Journal of Molecular & Cellular Cardiology, 37, 449-71 (2004)
doi:10.1016/j.yjmcc.2004.05.015
12. Hawkins, P. T., K. E. Anderson, K. Davidson & L. R. Stephens: Signalling through Class I PI3Ks in mammalian cells. Biochemical Society Transactions, 34, 647-62 (2006)
doi:10.1042/BST0340647
13. Adams, T. E., V. C. Epa, T. P. Garrett & C. W. Ward: Structure and function of the type 1 insulin-like growth factor receptor. Cellular & Molecular Life Sciences, 57, 1050-93 (2000)
doi:10.1007/PL00000744
14. Andrews, S., L. R. Stephens & P. T. Hawkins: PI3K class IB pathway. Science's Stke (Electronic Resource): Signal Transduction Knowledge Environment, 2007, cm2 (2007)
15. Naga Prasad, S. V., G. Esposito, L. Mao, W. J. Koch & H. A. Rockman: Gbetagamma-dependent phosphoinositide 3-kinase activation in hearts with in vivo pressure overload hypertrophy. Journal of Biological Chemistry, 275, 4693-8 (2000)
doi:10.1074/jbc.275.7.4693
16. Otani, H., T. Yamamura, Y. Nakao, R. Hattori, H. Kawaguchi, M. Osako & H. Imamura: Insulin-like growth factor-I improves recovery of cardiac performance during reperfusion in isolated rat heart by a wortmannin-sensitive mechanism. Journal of Cardiovascular Pharmacology, 35, 275-81 (2000)
doi:10.1097/00005344-200002000-00015
17. Mockridge, J. W., M. S. Marber & R. J. Heads: Activation of Akt during simulated ischemia/reperfusion in cardiac myocytes. Biochemical & Biophysical Research Communications, 270, 947-52 (2000)
doi:10.1006/bbrc.2000.2522
18. Jo, S.-H., V. Leblais, P. H. Wang, M. T. Crow & R.-P. Xiao: Phosphatidylinositol 3-kinase functionally compartmentalizes the concurrent G(s) signaling during beta2-adrenergic stimulation. Circulation Research, 91, 46-53 (2002)
doi:10.1161/01.RES.0000024115.67561.54
19. Kulik, G., A. Klippel & M. J. Weber: Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Molecular & Cellular Biology, 17, 1595-606 (1997)
20. Sun, H., G. Y. Oudit, R. J. Ramirez, D. Costantini & P. H. Backx: The phosphoinositide 3-kinase inhibitor LY294002 enhances cardiac myocyte contractility via a direct inhibition of Ik,slow currents. Cardiovascular Research, 62, 509-20 (2004)
doi:10.1016/j.cardiores.2004.01.029
21. McMullen, J. R. & G. L. Jennings: Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure. Clinical & Experimental Pharmacology & Physiology, 34, 255-62 (2007)
22. McMullen, J. R., T. Shioi, W. Y. Huang, L. Zhang, O. Tarnavski, E. Bisping, M. Schinke, S. Kong, M. C. Sherwood, J. Brown, L. Riggi, P. M. Kang & S. Izumo: The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase(p110alpha) pathway. Journal of Biological Chemistry, 279, 4782-93 (2004)
doi:10.1074/jbc.M310405200
23. McMullen, J. R., T. Shioi, L. Zhang, O. Tarnavski, M. C. Sherwood, P. M. Kang & S. Izumo: Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proceedings of the National Academy of Sciences of the United States of America, 100, 12355-60 (2003)
doi:10.1073/pnas.1934654100
24. Shioi, T., P. M. Kang, P. S. Douglas, J. Hampe, C. M. Yballe, J. Lawitts, L. C. Cantley & S. Izumo: The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO Journal, 19, 2537-48 (2000)
doi:10.1093/emboj/19.11.2537
25. Luo, J., J. R. McMullen, C. L. Sobkiw, L. Zhang, A. L. Dorfman, M. C. Sherwood, M. N. Logsdon, J. W. Horner, R. A. DePinho, S. Izumo & L. C. Cantley: Class IA phosphoinositide 3-kinase regulates heart size and physiological cardiac hypertrophy. Molecular & Cellular Biology, 25, 9491-502 (2005)
doi:10.1128/MCB.25.21.9491-9502.2005
26. Coleman, M. E., F. DeMayo, K. C. Yin, H. M. Lee, R. Geske, C. Montgomery & R. J. Schwartz: Myogenic vector expression of insulin-like growth factor I stimulates muscle cell differentiation and myofiber hypertrophy in transgenic mice. Journal of Biological Chemistry, 270, 12109-16 (1995)
doi:10.1074/jbc.270.20.12109
27. Chan, T. O., S. E. Rittenhouse & P. N. Tsichlis: AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annual Review of Biochemistry, 68, 965-1014 (1999)
doi:10.1146/annurev.biochem.68.1.965
28. DeBosch, B., I. Treskov, T. S. Lupu, C. Weinheimer, A. Kovacs, M. Courtois & A. J. Muslin: Akt1 is required for physiological cardiac growth. Circulation, 113, 2097-104 (2006)
doi:10.1161/CIRCULATIONAHA.105.595231
29. Oudit, G. Y., M. A. Crackower, U. Eriksson, R. Sarao, I. Kozieradzki, T. Sasaki, J. Irie-Sasaki, D. Gidrewicz, V. O. Rybin, T. Wada, S. F. Steinberg, P. H. Backx & J. M. Penninger: Phosphoinositide 3-kinase gamma-deficient mice are protected from isoproterenol-induced heart failure. Circulation, 108, 2147-52 (2003)
doi:10.1161/01.CIR.0000091403.62293.2B
30. Kerfant, B.-G., D. Zhao, I. Lorenzen-Schmidt, L. S. Wilson, S. Cai, S. R. W. Chen, D. H. Maurice & P. H. Backx: PI3Kgamma is required for PDE4, not PDE3, activity in subcellular microdomains containing the sarcoplasmic reticular calcium ATPase in cardiomyocytes. Circulation Research, 101, 400-8 (2007)
doi:10.1161/CIRCRESAHA.107.156422
31. Tasken, K. & E. M. Aandahl: Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiological Reviews, 84, 137-67 (2004)
doi:10.1152/physrev.00021.2003
32. Rose, R. A., M. G. Kabir & P. H. Backx: Altered heart rate and sinoatrial node function in mice lacking the cAMP regulator phosphoinositide 3-kinase-gamma. Circulation Research, 101, 1274-82 (2007)
doi:10.1161/CIRCRESAHA.107.158428
33. Maltsev, V. A. & E. G. Lakatta: Normal heart rhythm is initiated and regulated by an intracellular calcium clock within pacemaker cells. Heart, Lung & Circulation, 16, 335-48 (2007)
doi:10.1016/j.hlc.2007.07.005
34. Blatter, L. A., J. Kockskamper, K. A. Sheehan, A. V. Zima, J. Huser & S. L. Lipsius: Local calcium gradients during excitation-contraction coupling and alternans in atrial myocytes. Journal of Physiology, 546, 19-31 (2003)
doi:10.1113/jphysiol.2002.025239
35. Clark, R. A., S. McLennan, A. Dawson, D. Wilkinson & S. Stewart: Uncovering a hidden epidemic: a study of the current burden of heart failure in Australia. Heart, Lung & Circulation, 13, 266-73 (2004)
doi:10.1016/j.hlc.2004.06.007
36. Lilly, L. S.: Pathophysiology of heart disease: a collaborative project of medical students and faculty, 4th Edition. Lippincott Williams & Wilkins, Sydney (2007)
37. McMullen, J. R., J. Sadoshima & S. Izumo: Physiological versus pathological cardiac hypertrophy. In: Molecular Mechanisms of Cardiac Hypertrophy and Failure. Ed: R. A. Walsh. Taylor and Francis Group, London (2005)
38. Chien, K. R., K. U. Knowlton, H. Zhu & S. Chien: Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB Journal, 5, 3037-46 (1991)
39. Adams, J. W., Y. Sakata, M. G. Davis, V. P. Sah, Y. Wang, S. B. Liggett, K. R. Chien, J. H. Brown & G. W. Dorn, 2nd: Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proceedings of the National Academy of Sciences of the United States of America, 95, 10140-5 (1998)
doi:10.1073/pnas.95.17.10140
40. Sharma, A. K., S. Dhingra, N. Khaper & P. K. Singal: Activation of apoptotic processes during transition from hypertrophy to heart failure in guinea pigs.(see comment). American Journal of Physiology - Heart & Circulatory Physiology, 293, H1384-90 (2007)
doi:10.1152/ajpheart.00553.2007
41. McMullen, J. R., F. Amirahmadi, E. A. Woodcock, M. Schinke-Braun, R. D. Bouwman, K. A. Hewitt, J. P. Mollica, L. Zhang, Y. Zhang, T. Shioi, A. Buerger, S. Izumo, P. Y. Jay & G. L. Jennings: Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America, 104, 612-7 (2007)
doi:10.1073/pnas.0606663104
42. Crone, S. A., Y.-Y. Zhao, L. Fan, Y. Gu, S. Minamisawa, Y. Liu, K. L. Peterson, J. Chen, R. Kahn, G. Condorelli, J. Ross, Jr., K. R. Chien & K.-F. Lee: ErbB2 is essential in the prevention of dilated cardiomyopathy. Nature Medicine, 8, 459-65 (2002)
doi:10.1038/nm0502-459
43. Ozcelik, C., B. Erdmann, B. Pilz, N. Wettschureck, S. Britsch, N. Hubner, K. R. Chien, C. Birchmeier & A. N. Garratt: Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America, 99, 8880-5 (2002)
doi:10.1073/pnas.122249299
44. Dorn, G. W., 2nd, J. Robbins, N. Ball & R. A. Walsh: Myosin heavy chain regulation and myocyte contractile depression after LV hypertrophy in aortic-banded mice. American Journal of Physiology, 267, H400-5 (1994)
45. del Monte, F., S. E. Harding, U. Schmidt, T. Matsui, Z. B. Kang, G. W. Dec, J. K. Gwathmey, A. Rosenzweig & R. J. Hajjar: Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation, 100, 2308-11 (1999)
46. Izumo, S., B. Nadal-Ginard & V. Mahdavi: Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proceedings of the National Academy of Sciences of the United States of America, 85, 339-43 (1988)
doi:10.1073/pnas.85.2.339
47. Chien, K. R., H. Zhu, K. U. Knowlton, W. Miller-Hance, M. Van-Bilsen, T. X. O'Brien & S. M. Evans: Transcriptional regualtion during cardiac growth and development. Annual Review of Physiology, 55, 77-95 (1993)
doi:10.1146/annurev.ph.55.030193.000453
48. Nagai, R., A. Zarain-Herzberg, C. J. Brandl, J. Fujii, M. Tada, D. H. MacLennan, N. R. Alpert & M. Periasamy: Regulation of myocardial Ca2+-ATPase and phospholamban mRNA expression in response to pressure overload and thyroid hormone. Proceedings of the National Academy of Sciences of the United States of America, 86, 2966-70 (1989)
doi:10.1073/pnas.86.8.2966
49. Matsui, H., D. H. MacLennan, N. R. Alpert & M. Periasamy: Sarcoplasmic reticulum gene expression in pressure overload-induced cardiac hypertrophy in rabbit. American Journal of Physiology, 268, C252-8 (1995)
50. Arai, M., T. Suzuki & R. Nagai: Sarcoplasmic reticulum genes are upregulated in mild cardiac hypertrophy but downregulated in severe cardiac hypertrophy induced by pressure overload. Journal of Molecular & Cellular Cardiology, 28, 1583-90 (1996)
doi:10.1006/jmcc.1996.0149
51. Miyamoto, M. I., F. del Monte, U. Schmidt, T. S. DiSalvo, Z. B. Kang, T. Matsui, J. L. Guerrero, J. K. Gwathmey, A. Rosenzweig & R. J. Hajjar: Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure. Proceedings of the National Academy of Sciences of the United States of America, 97, 793-8 (2000)
doi:10.1073/pnas.97.2.793
52. Schultz, J. E. J., B. J. Glascock, S. A. Witt, M. L. Nieman, K. J. Nattamai, L. H. Liu, J. N. Lorenz, G. E. Shull, T. R. Kimball & M. Periasamy: Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity. American Journal of Physiology - Heart & Circulatory Physiology, 286, H1146-53 (2004)
doi:10.1152/ajpheart.00720.2003
53. Scheuer, J., A. Malhotra, C. Hirsch, J. Capasso & T. F. Schaible: Physiologic cardiac hypertrophy corrects contractile protein abnormalities associated with pathologic hypertrophy in rats. Journal of Clinical Investigation, 70, 1300-5 (1982)
doi:10.1172/JCI110729
54. Pieples, K., G. Arteaga, R. J. Solaro, I. Grupp, J. N. Lorenz, G. P. Boivin, G. Jagatheesan, E. Labitzke, P. P. DeTombe, J. P. Konhilas, T. C. Irving & D. F. Wieczorek: Tropomyosin 3 expression leads to hypercontractility and attenuates myofilament length-dependent Ca(2+) activation. American Journal of Physiology - Heart & Circulatory Physiology, 283, H1344-53 (2002)
55. Hewett, T. E., I. L. Grupp, G. Grupp & J. Robbins: Alpha-skeletal actin is associated with increased contractility in the mouse heart. Circulation Research, 74, 740-6 (1994)
56. Hart, M. C., Y. O. Korshunova & J. A. Cooper: Vertebrates have conserved capping protein alpha isoforms with specific expression patterns. Cell Motility & the Cytoskeleton, 38, 120-32 (1997)
doi:10.1002/(SICI)1097-0169(1997)38:2<120::AID-CM2>3.0.CO;2-B
57. Hart, M. C., Y. O. Korshunova & J. A. Cooper: Mapping of the mouse actin capping protein alpha subunit genes and pseudogenes. Genomics, 39, 264-70 (1997)
doi:10.1006/geno.1996.4506
58. Littlefield, R., A. Almenar-Queralt & V. M. Fowler: Actin dynamics at pointed ends regulates thin filament length in striated muscle. Nature Cell Biology, 3, 544-51 (2001)
doi:10.1038/35078517
59. Narula, J., N. Haider, R. Virmani, T. G. DiSalvo, F. D. Kolodgie, R. J. Hajjar, U. Schmidt, M. J. Semigran, G. W. Dec & B. A. Khaw: Apoptosis in myocytes in end-stage heart failure. New England Journal of Medicine, 335, 1182-9 (1996)
doi:10.1056/NEJM199610173351603
60. Sharov, V. G., H. N. Sabbah, H. Shimoyama, A. V. Goussev, M. Lesch & S. Goldstein: Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure. American Journal of Pathology, 148, 141-9 (1996)
61. Di Napoli, P., A. A. Taccardi, A. Grilli, M. Felaco, A. Balbone, D. Angelucci, S. Gallina, A. M. Calafiore, R. De Caterina & A. Barsotti: Left ventricular wall stress as a direct correlate of cardiomyocyte apoptosis in patients with severe dilated cardiomyopathy. American Heart Journal, 146, 1105-11 (2003)
doi:10.1016/S0002-8703(03)00445-9
62. Yao, R. & G. M. Cooper: Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science, 267, 2003-6 (1995)
doi:10.1126/science.7701324
63. Crowder, R. J. & R. S. Freeman: Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons. Journal of Neuroscience, 18, 2933-43 (1998)
64. Lee, W. L., J. W. Chen, C. T. Ting, T. Ishiwata, S. J. Lin, M. Korc & P. H. Wang: Insulin-like growth factor I improves cardiovascular function and suppresses apoptosis of cardiomyocytes in dilated cardiomyopathy. Endocrinology, 140, 4831-40 (1999)
doi:10.1210/en.140.10.4831
65. Li, Q., B. Li, X. Wang, A. Leri, K. P. Jana, Y. Liu, J. Kajstura, R. Baserga & P. Anversa: Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. Journal of Clinical Investigation, 100, 1991-9 (1997)
doi:10.1172/JCI119730
66. Datta, S. R., H. Dudek, X. Tao, S. Masters, H. Fu, Y. Gotoh & M. E. Greenberg: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 91, 231-41 (1997)
doi:10.1016/S0092-8674(00)80405-5
67. Cardone, M. H., N. Roy, H. R. Stennicke, G. S. Salvesen, T. F. Franke, E. Stanbridge, S. Frisch & J. C. Reed: Regulation of cell death protease caspase-9 by phosphorylation. Science, 282, 1318-21 (1998)
doi:10.1126/science.282.5392.1318
68. Kuwahara, K., Y. Saito, I. Kishimoto, Y. Miyamoto, M. Harada, E. Ogawa, I. Hamanaka, N. Kajiyama, N. Takahashi, T. Izumi, R. Kawakami & K. Nakao: Cardiotrophin-1 phosphorylates akt and BAD, and prolongs cell survival via a PI3K-dependent pathway in cardiac myocytes. Journal of Molecular & Cellular Cardiology, 32, 1385-94 (2000)
doi:10.1006/jmcc.2000.1177
69. Dhanasekaran, A., S. K. Gruenloh, J. N. Buonaccorsi, R. Zhang, G. J. Gross, J. R. Falck, P. K. Patel, E. R. Jacobs & M. Medhora: Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia. American Journal of Physiology - Heart & Circulatory Physiology, 294, H724-35 (2008)
doi:10.1152/ajpheart.00979.2007
70. Cook, S. A., P. H. Sugden & A. Clerk: Regulation of bcl-2 family proteins during development and in response to oxidative stress in cardiac myocytes: association with changes in mitochondrial membrane potential. Circulation Research, 85, 940-9 (1999)
71. Deveraux, Q. L., R. Takahashi, G. S. Salvesen & J. C. Reed: X-linked IAP is a direct inhibitor of cell-death proteases. Nature, 388, 300-4 (1997)
doi:10.1038/40901
72. Bakth, S., J. Arena, W. Lee, R. Torres, B. Haider, B. C. Patel, M. M. Lyons & T. J. Regan: Arrhythmia susceptibility and myocardial composition in diabetes. Influence of physical conditioning. Journal of Clinical Investigation, 77, 382-95 (1986)
doi:10.1172/JCI112316
73. Merx, W., M. S. Yoon & J. Han: The role of local disparity in conduction and recovery time on ventricular vulnerability to fibrillation. American Heart Journal, 94, 603-10 (1977)
doi:10.1016/S0002-8703(77)80130-0
74. Jalil, J. E., C. W. Doering, J. S. Janicki, R. Pick, S. G. Shroff & K. T. Weber: Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circulation Research, 64, 1041-50 (1989)
75. Perrino, C., J. N. Schroder, B. Lima, N. Villamizar, J. J. Nienaber, C. A. Milano & S. V. Naga Prasad: Dynamic regulation of phosphoinositide 3-kinase-gamma activity and beta-adrenergic receptor trafficking in end-stage human heart failure. Circulation, 116, 2571-9 (2007)
doi:10.1161/CIRCULATIONAHA.107.706515
76. Bristow, M. R., R. Ginsburg, W. Minobe, R. S. Cubicciotti, W. S. Sageman, K. Lurie, M. E. Billingham, D. C. Harrison & E. B. Stinson: Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. New England Journal of Medicine, 307, 205-11 (1982)
77. Naga Prasad, S. V., L. S. Barak, A. Rapacciuolo, M. G. Caron & H. A. Rockman: Agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane by beta-adrenergic receptor kinase 1. A role in receptor sequestration. Journal of Biological Chemistry, 276, 18953-9 (2001)
doi:10.1074/jbc.M102376200
78. Perrino, C., S. V. Naga Prasad, J. N. Schroder, J. A. Hata, C. Milano & H. A. Rockman: Restoration of beta-adrenergic receptor signaling and contractile function in heart failure by disruption of the betaARK1/phosphoinositide 3-kinase complex. Circulation, 111, 2579-87 (2005)
doi:10.1161/CIRCULATIONAHA.104.508796
79. Nienaber, J. J., H. Tachibana, S. V. Naga Prasad, G. Esposito, D. Wu, L. Mao & H. A. Rockman: Inhibition of receptor-localized PI3K preserves cardiac beta-adrenergic receptor function and ameliorates pressure overload heart failure. Journal of Clinical Investigation, 112, 1067-79 (2003)
80. Oudit, G. Y. & Z. Kassiri: Role of PI3 kinase gamma in excitation-contraction coupling and heart disease. Cardiovascular & Hematological Disorders Drug Targets, 7, 295-304 (2007)
81. Patrucco, E., A. Notte, L. Barberis, G. Selvetella, A. Maffei, M. Brancaccio, S. Marengo, G. Russo, O. Azzolino, S. D. Rybalkin, L. Silengo, F. Altruda, R. Wetzker, M. P. Wymann, G. Lembo & E. Hirsch: PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell, 118, 375-87 (2004)
doi:10.1016/j.cell.2004.07.017
Key Words: PI3K, Cardiac Hypertrophy, Heart Failure, Review
Send correspondence to: Julie R. McMullen, P.O. Box 6492, St Kilda Road Central, Melbourne, Victoria, 8008, Australia; Tel: 61-3-8532-1194, Fax: 61-3-8532-1100, E-mail: julie.mcmullen@bakeridi.edu.au