Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics

Circulation Research

Volumn 106, Issue 1, 2010, Pages 21-34

  Cheng, Hui ^a   Force, Thomas ^a  

^a THOMAS JEFFERSON UNIVERSITY   (United States)

Author keywords

Cancer; Cardiotoxicity; Kinase inhibitors; Therapeutics

Indexed keywords

AFINITOR; BCR ABL PROTEIN; BOSUTINIB; CD135 ANTIGEN; CEDIRANIB; DASATINIB; DEFOROLIMUS; ENZASTAURIN; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ERLOTINIB; EVEROLIMUS; FLAVOPIRIDOL; GEFITINIB; IMATINIB; JANUS KINASE 2; LAPATINIB; LESTAURTINIB; MAMMALIAN TARGET OF RAPAMYCIN; NILOTINIB; PAZOPANIB; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PROTEIN KINASE C BETA; PROTEIN TYROSINE KINASE; RAPAMYCIN; SORAFENIB; SUNITINIB; TEMSIROLIMUS; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANDETANIB; VASCULOTROPIN RECEPTOR 1;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LYMPHOCYTIC LEUKEMIA; ARTERY INJURY; BREAST CANCER; CANCER THERAPY; CARCINOGENESIS; CARDIOTOXICITY; CELL CYCLE REGULATION; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; CHRONIC MYELOMONOCYTIC LEUKEMIA; COLORECTAL CANCER; CONGESTIVE HEART FAILURE; DRUG MECHANISM; DRUG TARGETING; DRUG WITHDRAWAL; ENDOPLASMIC RETICULUM STRESS; ENZYME INHIBITION; GASTROINTESTINAL STROMAL TUMOR; GENE MUTATION; GLIOMA; HEART LEFT VENTRICLE EJECTION FRACTION; HEART LEFT VENTRICLE FAILURE; HEART VENTRICLE HYPERTROPHY; HUMAN; HYPEREOSINOPHILIC SYNDROME; HYPERTENSION; INSULIN DEPENDENT DIABETES MELLITUS; KIDNEY CARCINOMA; LARGE CELL LYMPHOMA; LIVER CELL CARCINOMA; LUNG NON SMALL CELL CANCER; METASTASIS; MYELOID METAPLASIA; MYELOPROLIFERATIVE DISORDER; NONHUMAN; OVARY CANCER; PANCREAS CANCER; POLYCYTHEMIA VERA; PRIORITY JOURNAL; PROTEIN FUNCTION; PULMONARY HYPERTENSION; RESTENOSIS; REVIEW; SARCOMA; SIDE EFFECT; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; CARDIOMEGALY; CARDIOTOXINS; CELL CYCLE; CELL SURVIVAL; DRUG DELIVERY SYSTEMS; HUMANS; MUSCLE PROTEINS; MYOCYTES, CARDIAC; NEOPLASM PROTEINS; NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTEIN KINASES; SIGNAL TRANSDUCTION;

EID: 74049125665     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.109.206920     Document Type: Review

References (81)

1. Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353:172-187.
2. Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardio-toxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007;7:332-344.
3. Norman P. Kinase therapeutic pipelines: an assessment of targets and agents in development. Insight Pharma Reports. 2007. Available at http://www.insightpharmareports.com/reports/2007/90-Kinase-Inhibitors/overview. asp.
4. Schwab M, Klempnauer KH, Alitalo K, Varmus H, Bishop M. Rearrangement at the 5' end of amplified c-myc in human COLO 320 cells is associated with abnormal transcription. Mol Cell Biol. 1986;6: 2752-2755.
5. Haber DA, Settleman J. Cancer: drivers and passengers. Nature. 2007; 446:145-146.
6. Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell. 2009;136:823-837.
7. Ma WW, Adjei AA. Novel agents on the horizon for cancer therapy. CA Cancer J Clin. 2009;59:111-137.
8. Sherbenou DW, Druker BJ. Applying the discovery of the Philadelphia chromosome. J Clin Invest. 2007;117:2067-2074.
9. Quintas-Cardama A, Kantarjian H, Cortes J. Flying under the radar: the new wave of BCR-ABL inhibitors. Nat Rev Drug Discov. 2007;6: 834-848.
10. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182-1186.
11. Folkman J. Angiogenesis: an organizing principle for drug discovery? Afa/ Rev Drug Discov. 2007;6:273-286.
12. Loges S, Schmidt T, Carmeliet P. 'Antimyeloangiogenic" therapy for cancer by inhibiting P1GF. Clin Cancer Res. 2009;15:3648-3653.
13. Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, Mathieson T, Perrin J, Raida M, Rau C, Reader V, Sweetman G, Bauer A, Bouwmeester T, Hopf C, Kruse U, Neubauer G, Ramsden N, Rick J, Kuster B, Drewes G. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol. 2007;25:1035-1044.
14. Ghoreschi K, Laurence A, O'Shea JJ. Selectivity and therapeutic inhibition of kinases: to be or not to be? Nat Immunol. 2009;10:356-360.
15. Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, Yan C, McConnell P, Spessard C, Banotai C, Mueller WT, Delaney A, Omer C, Sebolt-Leopold J, Dudley DT, Leung IK, Flamme C, Warmus J, Kaufman M, Barrett S, Tecle H, Hasemann CA. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol. 2004;11:1192-1197.
16. Okram B, Nagle A, Adrian FJ, Lee C, Ren P, Wang X, Sim T, Xie Y, Wang X, Xia G, Spraggon G, Warmuth M, Liu Y, Gray NS. A general strategy for creating "inactive-conformation" abl inhibitors. Chem Biol. 2006;13:779-786.
17. Sebolt-Leopold JS, Dudley DT, Herrera R, Van Becelaere K, Wiland A, Gowan RC, Tecle H, Barrett SD, Bridges A, Przybranowski S, Leopold WR, Saltiel AR. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med. 1999;5:810-816.
18. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497-5510.
19. Kerkela R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, Walters B, Shevtsov S, Pesant S, Clubb FJ, Rosenzweig A, Salomon RN, Van Etten RA, Alroy J, Durand JB, Force T. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908-916.
20. Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L, Woulfe K, Pravda E, Cassiola F, Desai J, George S, Morgan JA, Harris DM, Ismail NS, Chen JH, Schoen FJ, Van den Abbeele AD, Demetri GD, Force T, Chen MH. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370:2011-2019. (Pubitemid 350236338)
21. Schmidinger M, Zielinski CC, Vogl UM, Bojic A, Bojic M, Schukro C, Ruhsam M, Hejna M, Schmidinger H. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2008;26:5204-5212.
22. Fernandez A, Sanguino A, Peng Z, Ozturk E, Chen J, Crespo A, Wulf S, Shavrin A, Qin C, Ma J, Trent J, Lin Y, Han HD, Mangala LS, Bankson JA, Gelovani J, Samarel A, Bornmann W, Sood AK, Lopez-Berestein G. An anticancer c-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest. 2007;117:4044-4054.
23. Demetri GD. Structural reengineering of imatinib to decrease cardiac risk in cancer therapy. J Clin Invest. 2007;117:3650-3653.
24. Kerkela R, Woulfe KC, Durand JB, Vagnozzi R, Kramer D, Chu TF, Beahm C, Chen MH, Force T. Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. Clin TranslSci. 2009:1.
25. Liu L, Cash TP, JOnes RG, Keith B, Thompson CB, Simon MC. Hyp-oxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell. 2006;21:521-531.
26. Korennykh AV, Egea PF, Korostelev AA, Finer-Moore J, Zhang C, Shokat KM, Stroud RM, Walter P. The unfolded protein response signals through high-order assembly of Irel. Nature. 2009;457:687-693.
27. Potts MB, Vaugha AE, McDonough H, Patterson C, Deshmukh M. Reduced Apaf-1 levels in cardiomyocytes engage a strict regulation of apoptosis by endogenous XIAP. J Cell Biol. 2005;171:925-930.
28. Pentassuglia L, Graf M, Lane H, Kuramochi Y, Cote G, Timolati F, Sawyer DB, Zuppinger C, Suter TM. Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillar structural damage without cell death in adult rat cardiomyocytes. Exp Cell Res. 2009;315: 1302-1312.
29. Khakoo AY, Kassiotis CM, Tannir N, Plana JC, Halushka M, Bickford C, Trent J II, Champion JC, Durand JB, Lenihan DJ. Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer. 2008;112:2500-2508.
30. Izumiya Y, Shiojima I, Sato K, Sawyer DB, Colucci WS, Walsh K. Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload. Hypertension. 2006;47:887-893.
31. Sano M, Minamino T, Toko H, Miyauchi H, Orimo M, Qin Y, Akazawa H, Tateno K, Kayama Y, Harada M, Shimizu I, Asahara T, Hamada H, Tomita S, Molkentin JD, Zou Y, Komuro I. p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature. 2007; 446:444-448.
32. May D, Gilon D, Djonov V, Itin A, Lazarus A, Gordon O, Rosenberger C, Keshet E. Transgenic system for conditional induction and rescue of chronic myocardial hibernation provides insights into genomic programs of hibernation. Proc Natl Acad Sci USA. 2008;105:282-287.
33. Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene. 2008;27:5511-5526.
34. Liu W, Zhou Y, Reske SN, Shen C. PTEN mutation: many birds with one stone in tumorigenesis. Anticancer Res. 2008;28:3613-3619.
35. McMullen JR, Jay PY. PBK(pllOalpha) inhibitors as anti-cancer agents: minding the heart. Cell Cycle. 2007;6:910-913.
36. Mora A, Davies AM, Bertrand L, Sharif I, Budas GR, Jovanovic S. Mouton V, Kahn CR, Lucocq JM, Gray GA, Jovanovic A, Alessi DR. Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia. EMBO J. 2003;22:4666-4676.
37. Lawlor MA, Mora A, Ashby PR, Williams MR, Murray-Tait V, Malone L, Prescott AR, Lucocq JM, Alessi DR. Essential role of PDK1 in regulating cell size and development in mice. EMBO J. 2002;21: 3728-3738.
38. Ito K, Akazawa H, Tamagawa M, Furukawa K, Ogawa W, Yasuda N, Kudo Y, Liao CH, Yamamoto R, Sato T, Molkentin JD, Kasuga M, Noda T, Nakaya H, Komuro I. PDK1 coordinates survival pathways and beta-adrenergic response in the heart. Proc Natl Acad Sci USA. 2009; 106: 8689-8694.
39. Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J. 2008;412:179-190.
40. Shioi T, McMullen JR, Tarnavski O, Converso K, Sherwood MC, Manning WJ, Izumo S. Rapamycin attenuates load-induced hypertrophy in mice. Circulation. 2003;107:1664-1670.
41. Siedlecki AM, Jin X, Muslin A J. Uremic cardiac hypertrophy is reversed by rapamycin but not by lowering of blood pressure. Kidney Int. 2009; 75:800-808.
42. Parmacek MS, Epstein JA. Cardiomyocyte renewal. N Engl J Med. 2009;361:86-88.
43. Liem DA, Zhao P, Angelis E, Chan SS, Zhang J, Wang G, Berthet C, Kaldis P, Ping P, MacLellan WR. Cyclin-dependent kinase 2 signaling regulates myocardial ischemia/reperfusion injury. J Mol Cell Cardiol. 2008;45:610-616.
44. Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009;8:547-566.
45. Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Keys JR, Land vatter SW, Strickler JR McLaughlin MM, Siemens IR, Fisher SM, Livi GP, White JR, Adams JL, Young PR. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372:739-746.
46. Karcher SC, Laufer SA. Aza-analogue dibenzepinone scaffolds as p38 mitogen-activated protein kinase inhibitors: design, synthesis, and biological data of inhibitors with improved physicochemical properties. J Med Chem. 2009;52:1778-1782.
47. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685-1695.
48. Morris JB, Olzinski AR, Bernard RE, Aravindhan K, Mirabile RC, Boyce R, Willette RN, Jucker BM. p38 MAPK inhibition reduces aortic ultrasmall superparamagnetic iron oxide uptake in a mouse model of atherosclerosis: MRI assessment. Arterioscler Thromb Vase Biol. 2008; 28:265-271.
49. Sarov-Blat L, Morgan J, Fernandez P, James R, Lepore JJ, Fang Z, Sprecher DL. Inhibition of p38MAPK reduces inflammatory burden in subjects undergoing elective PCI. J Am Coll Cardiol. 2009;53: A419-A458.
50. West K. CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr Opin Investig Drugs. 2009; 10: 491-504.
51. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790. (Pubitemid 40570926)
52. Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE, Gozo M, McDowell EP, Levine RL, Doukas J, Mak CC, Noronha G, Martin M, Ko YD, Lee BH, Soil RM, Tefferi A, Hood JD, Gilliland DG. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2mu617F-induced polycythemia vera. Cancer Cell. 2008;13:311-320.
53. Manshouri T, Quintas-Cardama A, Nussenzveig RH, Gaikwad A, Estrov Z, Prchal J, Cortes JE, Kantarjian HM, Verstovsek S. The JAK kinase inhibitor CP-690,550 suppresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation. Cancer Sci. 2008;99: 1265-1273.
54. Xuan YT, Guo Y, Han H, Zhu Y, Bolli R. An essential role of the JAK-STAT pathway in ischemic preconditioning. Proc Natl Acad Sci USA. 2001;98:9050-9055.
55. Boengler K, Hilfiker-Kleiner D, Drexler H, Heusch G, Schulz R. The myocardial JAK/STAT pathway: from protection to failure. Pharmacol Ther. 2008;120:172-185.
56. Kurdi M, Booz GW. Can the protective actions of JAK-STAT in the heart be exploited therapeutically? Parsing the regulation of interleukin-6-type cytokine signaling. J Cardiovasc Pharmacol. 2007;50:126-141.
57. Louvet C, Szot GL, Lang J, Lee MR, Martinier N, Bollag G, Zhu S, Weiss A, Bluestone JA. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci USA. 2008;105: 18895-18900.
58. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W, Grimminger F. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;115:2811-2821.
59. Klein M, Schermuly RT, Ellinghaus P, Milting H, Riedl B, Nikolova S, Pullamsetti SS, Weissmann N, Dony E, Savai R, Ghofrani HA, Grimminger F, Busch AE, Schafer S. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation. 2008;118: 2081-2090.
60. Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, Lopez Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007;39:1007-1012.
61. Yamaguchi O, Watanabe T, Nishida K, Kashiwase K, Higuchi Y, Takeda T, Hikoso S, Hirotani S, Asahi M, Taniike M, Nakai A, Tsujimoto I, Matsumura Y, Miyazaki J, Chien KR, Matsuzawa A, Sadamitsu C, Ichijo H, Baccarani M, Hori M, Otsu K. Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J Clin Invest. 2004;114:937-943.
62. Harris IS, Zhang S, Treskov I, Kovacs A, Weinheimer C, Muslin AJ. Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload. Circulation. 2004; 110: 718-723.
63. Khakoo AY. Regulation of hypertrophic responses by PDGFR/3. American Heart Association, Basic Cardiovascular Sciences Annual Meeting, Lake Las Vegas, Nev, July 20-23, 2009.
64. Wang CH, Anderson N, Li SH, Szmitko PE, Cherng WJ, Fedak PW, Fazel S, Li RK, Yau TM, Weisel RD, Stanford WL, Verma S. Stem cell factor deficiency is vasculoprotective: unraveling a new therapeutic potential of imatinib mesylate. Circ Res. 2006;99:617-625.
65. Makiyama Y, Toba K, Kato K, Hirono S, Ozawa T, Saigawa T, Minagawa S, Isoda M, Asami F, Ikarashi N, Oda M, Moriyama M, Higashimura M, Kitajima T, Otaki K, Aizawa Y. Imatinib mesilate inhibits neointimal hyperplasia via growth inhibition of vascular smooth muscle cells in a rat model of balloon injury. Tohoku J Exp Med. 2008;215:299-306.
66. Ayach BB, Yoshimitsu M, Dawood F, Sun M, Arab S, Chen M, Higuchi K, Siatskas C, Lee P, Lim H, Zhang J, Cukerman E, Stanford WL, Medin JA, Liu PP. Stem cell factor receptor induces progenitor and natural killer cell-mediated cardiac survival and repair after myocardial infarction. Proc Natl Acad Sci USA. 2006;103:2304-2309.
67. Li M, Naqvi N, Yahiro E, Liu K, Powell PC, Bradley WE, Martin DL Graham RM, DellTtalia LJ, Husain A. c-kit is required for cardiomyocyte terminal differentiation. Circ Res. 2008;102:677-685.
68. Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008;7:1013-1030.
69. Land SC, Tee AR. Hypoxia-inducible factor lalpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J Biol Chem. 2007;282:20534-20543.
70. Noma T, Lemaire A, Naga Prasad SV, Barki-Harrington L, Tilley DG, Chen J, Le Corvoisier P, Violin JD, Wei H, Lefkowitz RJ, Rockman HA. Beta-arrestin-mediated betal-adrenergic receptor transactivation of the EGFR confers cardioprotection. J Clin Invest. 2007;117:2445-2458.
71. Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, Peterson KL, Chen J, Kahn R, Condorelli G, Ross J Jr, Chien KR, Lee KF. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med. 2002;8: 459-465.
72. Hsieh PC, MacGillvray C, Gannon J, Cruz FU, Lee RT. Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicity. Circulation. 2006; 114:637-644.
73. Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, Hirsch E, Suzuki A, Shioi T, Irie-Sasaki J, Sah R, Cheng H-YM, Rybin VO, Lembo G, Fratta L, Oliveira-dos-Santos AJ, Benovic JL, Kahn CR, Izumo S, Steinberg SF, Wyman MP, Backx PH, Penninger JM. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell. 2002;110:737-749.
74. Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD, Silengo L, Altruda F, Wetzker R, Wyman MP, Lembo G, Hirsch E. PI3Ky modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and-independent effects. Cell. 2004;118:375-387.
75. Muslin AJ, DeBosch B. Role of Akt in cardiac growth and metabolism. Novartis Found Symp. 2006;274:118-126.
76. Shiojima I, Yefremashvili M, Luo Z, Kureishi Y, Takahashi A, Tao J, Rosenzweig A, Kahn CR, Abel ED, Walsh K. Akt signaling mediates postnatal heart growth in response to insulin and nutritional status. J Biol Chem. 2002;277:37670-37677.
77. Matsui T, Nagoshi T, Hong EG, Luptak I, Hartil K, Li L, Gorovits N, Charron MJ, Kim JK, Tian R, Rosenzweig A. Effects of chronic Akt activation on glucose uptake in the heart. Am J Physiol Endocrinol Metab. 2006;290:E789-E797.
78. Gude N, Muraski J, Rubio M, Kajstura J, Schaefer E, Anversa P, Sussman MA. Akt promotes increased cardiomyocyte cycling and expansion of the cardiac progenitor cell population. Circ Res. 2006;99:381-388.
79. Snabaitis AK, Cuello F, Avkiran M. Protein kinase B/Akt phosphorylates and inhibits the cardiac Na+/H+ exchanger NHE1. Circ Res. 2008; 103: 881-890.
80. Bueno OF, Molkentin JD. Involvement of extracellular signal-regulated kinases 1/2 in cardiac hypertrophy and cell death. Circ Res. 2002;91: 776-781.
81. Ahuja P, Sdek P, Maclellan WR. Cardiac myocyte cell cycle control in development, disease, and regeneration. Physiol Rev. 2007;87: 521-544.