PI3K Inhibitors in Cardiovascular Disease

Cardiovascular Therapeutics

Volumn 29, Issue 1, 2011, Pages 29-36

  Eisenreich, Andreas ^a   Rauch, Ursula ^a  

^a CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

Author keywords

Coagulation Thrombosis; Molecular cardio biology; Valvular heart disease; Vascular biology

Indexed keywords

2 (2 DIFLUOROMETHYLBENZIMIDAZOL 1 YL) 4,6 DIMORPHOLINO 1,3,5 TRIAZINE; 2 (6 AMINO 9 PURINYLMETHYL) 5 METHYL 3 (2 METHYLPHENYL) 3H QUINAZOLIN 4 ONE; 2 MORPHOLINO 8 PHENYLCHROMONE; 5 (6 QUINOXALINYLMETHYLENE) 2,4 THIAZOLIDINEDIONE; 9 (1 ANILINOETHYL) 7 METHYL 2 MORPHOLINOPYRIDO[1,2 A]PYRIMIDIN 4 ONE; AS 604850; DEMETHOXYVIRIDIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE ALPHA; PHOSPHATIDYLINOSITOL 3 KINASE BETA; PHOSPHATIDYLINOSITOL 3 KINASE DELTA; PHOSPHATIDYLINOSITOL 3 KINASE GAMMA; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PIK 75; PIK 90; TG 100115; UNCLASSIFIED DRUG; WORTMANNIN;

ACUTE HEART INFARCTION; ANTIINFLAMMATORY ACTIVITY; ATHEROSCLEROTIC CARDIOVASCULAR DISEASE; CARDIOVASCULAR DISEASE; CELL CYCLE PROGRESSION; CELL MIGRATION; CELL MOTILITY; CELL SURVIVAL; ENZYME SUBUNIT; HEART INFARCTION; HEART SIZE; HOMEOSTASIS; HUMAN; METABOLIC REGULATION; NONHUMAN; PATHOGENESIS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; RNA TRANSLATION; THROMBOGENESIS; THROMBOSIS; TRANSCRIPTION REGULATION;

ANIMALS; ATHEROSCLEROSIS; CARDIOVASCULAR DISEASES; HUMANS; MYOCARDIAL INFARCTION; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; THROMBOSIS;

EID: 78751550507     PISSN: 17555914     EISSN: 17555922     Source Type: Journal    
DOI: 10.1111/j.1755-5922.2010.00206.x     Document Type: Review

References (84)

1. World Health Organization Program Fact Sheet #310: 2004 Death Rates. WHO international Web Site. Available from: [Assessed October 2008.
2. Myerburg RJ. Sudden cardiac death in persons with normal (or near normal) hearts. Am J Cardiol 1997;79:3-9.
3. Klein W. Cardiovascular disease at the turn of the millennium: Focus on Europe. Eur Heart J 2001;3(Suppl):M2-M6.
4. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics-2009 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009;119:e21-e181.
5. Rauch U, Osende JI, Fuster V, Badimon JJ, Fayad Z, Chesebro JH. Thrombus formation on atherosclerotic plaques: Pathogenesis and clinical consequences. Ann Intern Med 2001;134:224-238. Review.
6. Stellbaum C, Willich T, Boltzen U, et al. Clopidogrel-mediated reduction of circulating tissue factor in patients with stable coronary artery disease. Eur J Haematol 2007;78:347-352.
7. Eisenreich A, Celebi O, Goldin-Lang P, Schultheiss HP, Rauch U. Upregulation of tissue factor expression and thrombogenic activity in human aortic smooth muscle cells by irradiation, rapamycin and paclitaxel. Int Immunopharmacol 2008;8:307-311.
8. Kuwahata S, Fujita S, Orihara K, et al. High expression level of Toll-like receptor 2 on monocytes is an important risk factor for arteriosclerotic disease. Atherosclerosis 2010;209:208-254.
9. Szotowski B, Goldin-Lang P, Antoniak S, et al. Alterations in myocardial tissue factor expression and cellular localization in dilated cardiomyopathy. J Am Coll Cardiol 2005;45:1081-1089.
10. Pachori AS, Custer L, Hansen D, Clapp S, Kemppa E, Klingensmith J. Bone Morphogenetic Protein 4 mediates myocardial ischemic injury through JNK dependent signaling pathway. J Mol Cell Cardiol 2010;48:1255-1265.
11. Siragusa M, Katare R, Meloni M, Damilano F, Hirsch E, Emanueli C, Madeddu P. Involvement of Phosphoinositide 3-Kinase {gamma} in Angiogenesis and Healing of Experimental Myocardial Infarction in Mice. Circ Res 2010;106:757-768.
12. Bulhak AA, Jung C, Ostenson CG, Lundberg JO, Sjöquist PO, Pernow J. PPAR-alpha activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: Involvement of the PI3-Kinase/Akt and NO pathway. Am J Physiol Heart Circ Physiol 2009;296:H719-H727.
13. Choi KH, Kim JE, Song NR, et al. Phosphoinositide-3-kinase is a novel target of piceatannol for inhibiting PDGF-BB-induced proliferation and migration in human aortic smooth muscle cells. Cardiovasc Res 2009;85:836-844.
14. Liu J, Lin B, Hao Y, et al. Lewis y antigen promotes the proliferation of ovarian carcinoma-derived RMG-I cells through the PI3K/Akt signaling pathway. J Exp Clin Cancer Res 2009;28:154.
15. Fruman DA, Bismuth G. Fine tuning the immune response with PI3K. Immunol Rev 2009;228:253-372. Review.
16. Maira SM, Stauffer F, Schnell C, García-Echeverría C. PI3K inhibitors for cancer treatment: Where do we stand? Biochem Soc Trans 2009;37:265-272. Review.
17. Whitman M, Kaplan DR, Schaffhausen B, Cantley L, Roberts TM. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 1985;315:239-242.
18. Whitman M, Downes CP, Keeler M, Keller T, Cantley L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature 1988;332:644-646.
19. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489-501. Review.
20. Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res 2009;102:19-65. Review.
21. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655-1657. Review.
22. Vanhaesebroeck B, Leevers SJ, Ahmadi K, et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 2001;70:535-602. Review.
23. Rommel C, Camps M, Ji H. PI3K delta and PI3K gamma: Partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol 2007;7:191-201. Review.
24. Breitenstein A, Camici GG, Tanner FC. Tissue factor: Beyond coagulation in the cardiovascular system. Clin Sci (Lond) 2009;118:159-172. Review.
25. Wymann MP, Zvelebil M, Laffargue M. Phosphoinositide 3-kinase signalling-which way to target?. Trends Pharmacol Sci 2003;24:366-376. Review.
26. Wheeler M, Domin J. Recruitment of the class II phosphoinositide 3-kinase C2b to the epidermal growth factor receptor: Role of Grb2. Mol Cell Biol 2001;21:6660-6667.
27. Arcaro A, Khanzada U, Vanhaesebroeck B, Tetley TD, Waterfield MD, Seckl MJ. Two distinct phosphoinositide 3-kinases mediate polypeptide growth factor-stimulated PKB activation. EMBO J 2002;21:5097-5108.
28. Hirsch E, Ciraolo E, Ghigo A, Costa C. Taming the PI3K team to hold inflammation and cancer at bay. Pharmacol Ther 2008;118:192-205. Review.
29. Shiojima I, Walsh K. Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 2002;90:1243-1250. Review.
30. Eisenreich A, Malz R, Pepke W, Ayral Y, Poller W, Schultheiss HP, Rauch U. Role of the phosphatidylinositol 3-kinase/protein kinase B pathway in regulating alternative splicing of tissue factor mRNA in human endothelial cells. Circ J 2009;73:1746-1752.
31. Leevers SJ, Weinkove D, MacDougall LK, Hafen E, Waterfield MD. The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J 1996;15:6584-6594.
32. Shioi T, Kang PM, Douglas PS, et al. The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J 2000;19:2537-2548.
33. Shioi T, McMullen JR, Kang PM, et al. Akt/protein kinase B promotes organ growth in transgenic mice. Mol Cell Biol 2002;22:2799-2809.
34. Luo J, McMullen JR, Sobkiw CL, et al. Class IA phosphoinositide 3-kinase regulates heart size and physiological cardiac hypertrophy. Mol Cell Biol 2005;25:9491-9502.
35. Crackower MA, Oudit GY, Kozieradzki I, et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 2002;110:737-749.
36. Alloatti G, Levi R, Malan D, et al. Phosphoinositide 3-kinase gamma-deficient hearts are protected from the PAF-dependent depression of cardiac contractility. Cardiovasc Res 2003;60:242-249.
37. Alloatti G, Marcantoni A, Levi R, et al. Phosphoinositide 3-kinase gamma controls autonomic regulation of the mouse heart through Gi-independent downregulation of cAMP level. FEBS Lett 2005;579:133-140.
38. Patrucco E, Notte A, Barberis L, et al. PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 2004;118(3):375-387.
39. Doukas J, Wrasidlo W, Noronha G, et al. Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury. Proc Natl Acad Sci U S A 2006;103:19866-19871.
40. Chavakis E, Carmona G, Urbich C, et al. Phosphatidylinositol-3-kinase gamma is integral to homing functions of progenitor cells. Circ Res 2008;102:942-949.
41. Madeddu P, Kraenkel N, Barcelos LS, et al. Phosphoinositide 3-kinase gamma gene knockout impairs post-ischemic neovascularization and endothelial progenitor cell functions. Arterioscler Thromb Vasc Biol 2008;28:68-76.
42. Rittenhouse SE. Phosphoinositide 3-kinase activation and platelet function. Blood 1996;88:4401-4414. Review.
43. Hirsch E, Bosco O, Tropel P, et al. Resistance to thromboembolism in PI3Kgamma-deficient mice. FASEB J 2001;15:2019-2021.
44. Gilio K, Munnix IC, Mangin P, et al. Non-redundant roles of phosphoinositide 3-kinase isoforms alpha and beta in glycoprotein VI-induced platelet signaling and thrombus formation. J Biol Chem 2009;284:33750-33762.
45. Shah PK. Inflammation and plaque vulnerability. Cardiovasc Drugs Ther 2009;23:31-40.
46. Kim JY, Kim WJ, Kim H, Suk K, Lee WH. The Stimulation of CD147 Induces MMP-9 Expression through ERK and NF-kappaB in Macrophages: Implication for Atherosclerosis. Immune Netw 2009;9:90-97.
47. Barberis L, Hirsch E. Targeting phosphoinositide 3-kinase gamma to fight inflammation and more. Thromb Haemost 2008;99:279-285. Review.
48. Wiesinger D, Gubler HU, Haefliger W, Hauser D. Antiinflammatory activity of the new mould metabolite 11-desacetoxy-wortmannin and of some of its derivatives. Experientia 1974;30:135-136.
49. Arcaro A, Wymann MP. Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: The role of phosphatidylinositol 3, 4, 5-trisphosphate in neutrophil responses. Biochem J 1993;296:297-301.
50. Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, Pirola L, Vanhaesebroeck B, Waterfield MD, Panayotou G. Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol Cell Biol 1996;16:1722-1733.
51. Vlahos CJ, Matter WF, Hui KY, Brown RF. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 1994;269:5241-5248.
52. Ward SG, June CH, Olive D. PI 3-kinase: A pivotal pathway in T-cell activation?. Immunol Today 1996;17:187-197. Review.
53. Brunn GJ, Williams J, Sabers C, Wiederrecht G, Lawrence JC Jr, Abraham RT. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J 1996;15:5256-5267.
54. Gharbi SI, Zvelebil MJ, Shuttleworth SJ, Hancox T, Saghir N, Timms JF, Waterfield MD. Exploring the specificity of the PI3K family inhibitor LY294002. Biochem J 2007;404:15-21.
55. Sun H, Oudit GY, Ramirez RJ, Costantini D, Backx PH. The phosphoinositide 3-kinase inhibitor LY294002 enhances cardiac myocyte contractility via a direct inhibition of Ik, slow currents. Cardiovasc Res 2004;62:509-520.
56. Li B, Liu Y, Uno T, Gray N. Creating chemical diversity to target protein kinases. Comb Chem High Throughput Screen 2004;7:453-472. Review.
57. Toledo LM, Lydon NB, Elbaum D. The structure-based design of ATP-site directed protein kinase inhibitors. Curr Med Chem 1999;6:775-805. Review.
58. Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 2000;6:909-919.
59. Sadhu C, Masinovsky B, Dick K, Sowell CG, Staunton DE. Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement. J Immunol 2003;170:2647-2654.
60. Puri KD, Doggett TA, Douangpanya J, et al. Mechanisms and implications of phosphoinositide 3-kinase delta in promoting neutrophil trafficking into inflamed tissue. Blood 2004;103:3448-3456.
61. Camps M, Rückle T, Ji H, et al. Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med 2005;11:936-943.
62. Hayakawa M, Kaizawa H, Moritomo H, et al. Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110alpha inhibitors. Bioorg Med Chem 2006;14:6847-6858.
63. Knight ZA, Gonzalez B, Feldman ME, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 2006;125:733-747.
64. Palanki MS, Dneprovskaia E, Doukas J, et al. Discovery of 3, 3-(2, 4-diaminopteridine-6, 7-diyl)diphenol as an isozyme-selective inhibitor of PI3K for the treatment of ischemia reperfusion injury associated with myocardial infarction. J Med Chem 2007;50:4279-4294.
65. Yaguchi S, Fukui Y, Koshimizu I, et al. Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst 2006;98:5455-5456.
66. Kong D, Okamura M, Yoshimi H, Yamori T. Antiangiogenic effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor. Eur J Cancer 2009;45:857-865.
67. Wallentin L, Becker RC, Budaj A, et al. PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-1057.
68. Manoharan A, Gemmell R, Hartwell T. Use of whole blood platelet lumi-aggregometry to optimize anti-platelet therapy in patients with chronic myeloproliferative disorders. Am J Hematol 2006;81:676-683.
69. Eisenreich A, Bogdanov VY, Zakrzewicz A, et al. Cdc2-like kinases and DNA topoisomerase I regulate alternative splicing of tissue factor in human endothelial cells. Circ Res 2009;104:589-599.
70. Ohman MK, Eitzman DT. Targeting MCP-1 to reduce vascular complications of obesity. Recent Pat Cardiovasc Drug Discov 2009;4:164-176.
71. Heroux J, Gharib AM, Danthi NS, Cecchini S, Ohayon J, Pettigrew RI. High-Affinity alpha v beta 3 integrin targeted optical probe as a new imaging biomarker for early atherosclerosis: Initial studies in Watanabe rabbits. Mol Imaging Biol 2010;12:2-8.
72. Wu Y, Zhang R, Zhou C, et al. Enhanced expression of vascular cell adhesion molecule-1 by corticotrophin-releasing hormone contributes to progression of atherosclerosis in LDL receptor-deficient mice. Atherosclerosis 2009;203:360-370.
73. von Schlieffen E, Oskolkova OV, Schabbauer G, et al. Multi-hit inhibition of circulating and cell-associated components of the toll-like receptor 4 pathway by oxidized phospholipids. Arterioscler Thromb Vasc Biol 2009;29:356-362.
74. Rydberg C, Månsson A, Uddman R, Riesbeck K, Cardell LO. Toll-like receptor agonists induce inflammation and cell death in a model of head and neck squamous cell carcinomas. Immunology 2009;128(1 Suppl):e600-e611.
75. Graupera M, Guillermet-Guibert J, Foukas LC, et al. Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature 2008;453:662-666.
76. Boullier A, Li Y, Quehenberger O, Palinski W, Tabas I, Witztum JL, Miller YI. Minimally oxidized LDL offsets the apoptotic effects of extensively oxidized LDL and free cholesterol in macrophages. Arterioscler Thromb Vasc Biol 2006;26:1169-1176.
77. Rückle T, Schwarz MK, Rommel C. PI3Kgamma inhibition: Towards an 'aspirin of the 21st century'?. Nat Rev Drug Discov 2006;5:903-918. Review.
78. Fougerat A, Gayral S, Gourdy P, et al. Genetic and pharmacological targeting of phosphoinositide 3-kinase-gamma reduces atherosclerosis and favors plaque stability by modulating inflammatory processes. Circulation 2008;117:1310-1307.
79. Chang JD, Sukhova GK, Libby P, et al. Deletion of the phosphoinositide 3-kinase p110gamma gene attenuates murine atherosclerosis. Proc Natl Acad Sci U S A 2007;104:8077-8082.
80. MacDonald PE, Joseph JW, Yau D, et al. Impaired glucose-stimulated insulin secretion, enhanced intraperitoneal insulin tolerance, and increased beta-cell mass in mice lacking the p110gamma isoform of phosphoinositide 3-kinase. Endocrinology 2004;145:4078-4083.
81. Curcio A, Noma T, Naga Prasad SV, et al. Competitive displacement of phosphoinositide 3-kinase from beta-adrenergic receptor kinase-1 improves postinfarction adverse myocardial remodeling. Am J Physiol Heart Circ Physiol 2006;291:H1754-H1760.
82. http://clinicaltrials.gov/ct/show/NCT00103350?order=1.
83. Kim S, Mangin P, Dangelmaier C, Lillian R, Jackson SP, Daniel JL, Kunapuli SP. Role of phosphoinositide 3-kinase beta in glycoprotein VI-mediated Akt activation in platelets. J Biol Chem 2009;284:33763-33772.
84. Sturgeon SA, Jones C, Angus JA, Wright CE. Advantages of a selective beta-isoform phosphoinositide 3-kinase antagonist, an anti-thrombotic agent devoid of other cardiovascular actions in the rat. Eur J Pharmacol 2008;587:209-215.