Mechanisms of Cardiac Hypertrophy and the Development of Heart Failure

Role of Insulin-Like Growth Factor-I and Angiotensin-II
  • Patrice Delafontaine
  • Marijke Brink
  • Yao-Hua Song
Part of the Nutrition and Health book series (NH)


  • The RAS and the IGF-I system interact at multiple levels to regulate physiological and pathological cardiac growth responses.

  • IGF-I promotes growth and survival of cardiac and skeletal muscle which is salutary in heart failure.

  • AngII down regulates circulating and skeletal muscle IGF-I and IGF binding proteins, leading to increased myocardial apoptosis and increased skeletal muscle proteolysis.

  • Preliminary studies reveal significant alterations in the IGF-I system in heart failure.

  • An imbalance between the RAS and the IGF-I system contributes to the progression from compensated to decompensated heart failure.


Heart Failure Growth Hormone Chronic Heart Failure Cardiac Hypertrophy Insulin Growth Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Colucci WS and Braunwald E. Pathophysiology of heart failure. In: Heart Disease: 6th ed. Braunwald E, Zipes DP, and Libby P (eds.). W.B. Saunders, Philadelphia, PA, 2001. p. 503–533.Google Scholar
  2. 2.
    Hefti MA, Harder BA, Eppenberger HM, Schaub MC. Signaling pathways in cardiac myocyte hypertrophy. J Mol Cell Cardiol 1997; 29: 2873–2892.PubMedCrossRefGoogle Scholar
  3. 3.
    Sorescu D, Griendling KK. Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Fail 2002; 8: 132–140.PubMedCrossRefGoogle Scholar
  4. 4.
    Sugden PH. Signalling pathways in cardiac myocyte hypertrophy. Ann Med 2001; 33: 611–622.PubMedGoogle Scholar
  5. 5.
    Lisman KA, Stetson SJ, Koerner MM, Farmer JA, Torre-Amione G. The role of tumor necrosis factor alpha blockade in the treatment of congestive heart failure. Congest Heart Fail 2002; 8: 275–279.PubMedCrossRefGoogle Scholar
  6. 6.
    Sack M. Tumor necrosis factor-alpha in cardiovascular biology and the potential role for anti-tumor necrosis factor-alpha therapy in heart disease. Pharmacol Ther 2002; 94: 123–135.PubMedCrossRefGoogle Scholar
  7. 7.
    Grounds MD. Reasons for the degeneration of ageing skeletal muscle: a central role for IGF-1 signalling. Biogerontology 2002; 3: 19–24.PubMedCrossRefGoogle Scholar
  8. Greenberg B. Treatment of heart failure: state of the art and prospectives. J Cardiovasc Pharmacol 2001;38 Supp12:S59–S63.Google Scholar
  9. 9.
    Hollenberg NK. Impact of angiotensin II on the kidney: does an angiotensin II receptor blocker make sense? Am J Kidney Dis 2000; 36: 518 - S23.CrossRefGoogle Scholar
  10. 10.
    Sayeski PP, Ali MS, Semeniuk DJ, Doan TN, Bernstein KE. Angiotensin II signal transduction pathways. Regul Pept 1998; 78: 19–29.PubMedCrossRefGoogle Scholar
  11. Unger T. The role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol 2002;89:3A–9A; discussion 10A.Google Scholar
  12. 12.
    Opie LH, Sack MN. Enhanced angiotensin II activity in heart failure: reevaluation of the counterregulatory hypothesis of receptor subtypes. Circ Res 2001; 88: 654–658.PubMedCrossRefGoogle Scholar
  13. 13.
    Harada K, Sugaya T, Murakami K, Yazaki Y, Komuro I. Angiotensin II type lA receptor knockout mice display less left ventricular remodeling and improved survival after myocardial infarction. Circulation 1999; 100: 2093–2099.PubMedCrossRefGoogle Scholar
  14. 14.
    Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G. ACE inhibitor use in patients with myocardial infarction. Summary of evidence from clinical trials. Circulation 1995; 92: 3132–3137.PubMedCrossRefGoogle Scholar
  15. 15.
    Dahlof B. Regression of left ventricular hypertrophy-are there differences between antihypertensive agents? Cardiology 1992; 81: 307–315.PubMedCrossRefGoogle Scholar
  16. 16.
    Zuanetti G, Latini R, Maggioni AP, Franzosi M, Santoro L, Tognoni G. Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: data from the GISSI-3 study. Circulation 1997; 96: 4239–4245.PubMedCrossRefGoogle Scholar
  17. 17.
    Nomoto T, Nishina T, Miwa S, et al. Angiotensin-converting enzyme inhibitor helps prevent late remodeling after left ventricular aneurysm repair in rats. Circulation 2002; 106: I115 - I119.PubMedGoogle Scholar
  18. 18.
    Kanno S, Wu YJ, Lee PC, Billiar TR, Ho C. Angiotensin-converting enzyme inhibitor preserves p21 and endothelial nitric oxide synthase expression in monocrotaline-induced pulmonary arterial hypertension in rats. Circulation 2001; 104: 945–950.PubMedCrossRefGoogle Scholar
  19. 19.
    Iwanaga Y, Kihara Y, Inagaki K, et al. Differential effects of angiotensin II versus endothelin-1 inhibitions in hypertrophic left ventricular myocardium during transition to heart failure. Circulation 2001; 104: 606–612.PubMedCrossRefGoogle Scholar
  20. 20.
    Givertz MM. Manipulation of the renin-angiotensin system. Circulation 2001; 104: E14 - E18.PubMedCrossRefGoogle Scholar
  21. 21.
    Lindpaintner K, Jin MW, Niedermaier N, Wilhelm MJ, Ganten D. Cardiac angiotensinogen and its local activation in the isolated perfused beating heart. Circ Res 1990; 67: 564–573.PubMedCrossRefGoogle Scholar
  22. 22.
    Danser AH, van Kats JP, Admiraal PJ, et al. Cardiac renn and angiotensins. Uptake from plasma versus in situ synthesis. Hypertension 1994; 24: 37–48.PubMedCrossRefGoogle Scholar
  23. 23.
    Sawa H, Tokuchi F, Mochizuki N, et al. Expression of the angiotensinogen gene and localization of its protein in the human heart. Circulation 1992; 86: 138–146.PubMedCrossRefGoogle Scholar
  24. 24.
    Lindpaintner K, Lu W, Neidermajer N, et al. Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat. J Mol Cell Cardiol 1993; 25: 133–143.PubMedCrossRefGoogle Scholar
  25. 25.
    Schunkert H, Dzau VJ, Tang SS, Hirsch AT, Apstein CS, Lorell BH. Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. Effects on coronary resistance, contractility, and relaxation. J Clin Invest 1990; 86: 1913–1920.PubMedCrossRefGoogle Scholar
  26. 26.
    Studer R, Reinecke H, Muller B, Holtz J, Just H, Drexler H. Increased angiotensin-I converting enzyme gene expression in the failing human heart. Quantification by competitive RNA polymerise chain reaction. J Clin Invest 1994; 94: 301–310.PubMedCrossRefGoogle Scholar
  27. 27.
    Hokimoto S, Yasue H, Fujimoto K, Sakata R, Miyamoto E. Increased angiotensin converting enzyme activity in left ventricular aneurysm of patients after myocardial infarction. Cardiovasc Res 1995; 29: 664–669.PubMedGoogle Scholar
  28. 28.
    Egido J. Vasoactive hormones and renal sclerosis. Kidney Int 1996; 49: 578–597.PubMedCrossRefGoogle Scholar
  29. 29.
    Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin II and renal fibrosis. Hypertension 2001; 38: 635–638.PubMedCrossRefGoogle Scholar
  30. 30.
    Matsubara H. Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases. Circ Res 1998; 83: 1182–1191.PubMedCrossRefGoogle Scholar
  31. 31.
    Sadoshima J. Cytokine actions of angiotensin II. Circ Res 2000; 86: 1187–1189.PubMedCrossRefGoogle Scholar
  32. 32.
    Leri A, Claudio PP, Li Q, Li P, Cheng W, Meggs LG, et al. Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. J Clin Invest 1998; 101: 1326–1342.PubMedCrossRefGoogle Scholar
  33. 33.
    Kajstura J, Cigola E, Malhotra A, Li P, Cheng W, Meggs LG, et al. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. J Mol Cell Cardiol 1997; 29: 859–870.PubMedCrossRefGoogle Scholar
  34. 34.
    Baxter RC. Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. Am J Physiol Endocrinol Metab 2000; 278: E967 - E976.PubMedGoogle Scholar
  35. 35.
    Binoux M, Hossenlopp P, Hardouin S, Seurin D, Lassarre C, Gourmelen M. Somatomedin (insulin-like growth factors)-binding proteins. Molecular forms and regulation. Horm Res 1986; 24: 141–151.PubMedCrossRefGoogle Scholar
  36. 36.
    Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 2002; 23: 824–854.PubMedCrossRefGoogle Scholar
  37. 37.
    Lund PK, Moats-Staats BM, Hynes MA, et al. Somatomedin-C/insulin-like growth factor-I and insulin-like growth factor-II mRNAs in rat fetal and adult tissues. J Biol Chem 1986; 261: 14539–14544.PubMedGoogle Scholar
  38. 38.
    Delafontaine P. Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc Res 1995; 30: 825–834.PubMedGoogle Scholar
  39. 39.
    Khorsandi MJ, Fagin JA, Giannella-Neto D, Forrester JS, Cercek B. Regulation of insulin-like growth factor-I and its receptor in rat aorta after balloon denudation. Evidence for local bioactivity. J Clin Invest 1992; 90: 1926–1931.PubMedCrossRefGoogle Scholar
  40. 40.
    Lopez-Fernandez J, Sanchez-Franco F, Velasco B, Tolon RM, Pazos F, Cacicedo L. Growth hormone induces somatostatin and insulin-like growth factor I gene expression in the cerebral hemispheres of aging rats. Endocrinology 1996; 137: 4384–4391.PubMedCrossRefGoogle Scholar
  41. 41.
    Murphy LJ, Friesen HG. Differential effects of estrogen and growth hormone on uterine and hepatic insulin-like growth factor I gene expression in the ovariectomized hypophysectomized rat. Endocrinology 1988; 122: 325–232.PubMedCrossRefGoogle Scholar
  42. 42.
    Yamamoto H, Murphy LJ. Enzymatic conversion of IGF-I to des(1–3)IGF-I in rat serum and tissues: a further potential site of growth hormone regulation of IGF-I action. J Endocrinol 1995; 146: 141–148.PubMedCrossRefGoogle Scholar
  43. 43.
    LeRoith D, Werner H, Beitner-Johnson D, Roberts CT, Jr. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 1995; 16: 143–163.PubMedGoogle Scholar
  44. 44.
    Tseng YH, Ueki K, Kriauciunas KM, Kahn CR. Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. J Biol Chem 2002; 277: 31601–31611.PubMedCrossRefGoogle Scholar
  45. 45.
    Ueki K, Fruman DA, Brachmann SM, Tseng YH, Cantley LC, Kahn CR. Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol Cell Biol 2002; 22: 965–977.PubMedCrossRefGoogle Scholar
  46. 46.
    Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995; 16: 3–34.PubMedGoogle Scholar
  47. 47.
    Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igflr). Cell 1993; 75: 59–72.PubMedGoogle Scholar
  48. 48.
    Baker J, Liu JP, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell 1993; 75: 73–82.PubMedGoogle Scholar
  49. 49.
    Skrtic S, Wallenius K, Sjogren K, Isaksson OG, Ohlsson C, Jansson JO. Possible roles of insulin-like growth factor in regulation of physiological and pathophysiological liver growth. Horm Res 2001; 55 (Suppl 1): 1–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Ye P, Li L, Richards RG, DiAugustine RP, D’Ercole AJ. Myelination is altered in insulin-like growth factor-I null mutant mice. J Neurosci 2002; 22: 6041–6051.PubMedGoogle Scholar
  51. 51.
    Camarero G, Avendano C, Fernandez-Moreno C, et al. Delayed inner ear maturation and neuronal loss in postnatal Igf-1-deficient mice. J Neurosci 2001; 21: 7630–7641.PubMedGoogle Scholar
  52. 52.
    Kido Y, Nakae J, Hribal ML, Xuan S, Efstratiadis A, Accili D. Effects of mutations in the insulin-like growth factor signaling system on embryonic pancreas development and beta-cell compensation to insulin resistance. J Biol Chem 2002; 277: 36740–36747.PubMedCrossRefGoogle Scholar
  53. 53.
    Kadakia R, Arraztoa JA, Bondy C, Zhou J. Granulosa cell proliferation is impaired in the Igfl null ovary. Growth Horm IGF Res 2001; 11: 220–224.PubMedCrossRefGoogle Scholar
  54. 54.
    Liu JL, LeRoith D. Insulin-like growth factor I is essential for postnatal growth in response to growth hormone. Endocrinology 1999; 140: 5178–5184.PubMedCrossRefGoogle Scholar
  55. 55.
    Ruan W, Kleinberg DL. Insulin-like growth factor I is essential for terminal end bud formation and ductal morphogenesis during mammary development. Endocrinology 1999; 140: 5075–5081.PubMedCrossRefGoogle Scholar
  56. 56.
    DeChiara TM, Efstratiadis A, Robertson EJ. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 1990; 345: 78–80.PubMedCrossRefGoogle Scholar
  57. 57.
    DeChiara TM, Robertson EJ, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell 1991; 64: 849–859.PubMedCrossRefGoogle Scholar
  58. 58.
    Ren J, Samson WK, Sowers JR. Insulin-like growth factor I as a cardiac hormone: physiological and pathophysiological implications in heart disease. J Mol Cell Cardiol 1999; 31: 2049–2061.PubMedCrossRefGoogle Scholar
  59. 59.
    Khan AS, Sane DC, Wannenburg T, Sonntag WE. Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system. Cardiovasc Res 2002; 54: 25–35.PubMedCrossRefGoogle Scholar
  60. 60.
    Norby FL, Wold LE, Duan J, Hintz KK, Ren J. IGF-I attenuates diabetes-induced cardiac contractile dysfunction in ventricular myocytes. Am J Physiol Endocrinol Metab 2002: 283: E658 - E666.PubMedGoogle Scholar
  61. 61.
    Tivesten A, Caidahl K, Kujacic V, et al. Similar cardiovascular effects of growth hormone and insulin-like growth factor-I in rats after experimental myocardial infarction. Growth Horm IGF Res 2001; 11: 187–195.PubMedCrossRefGoogle Scholar
  62. 62.
    Parrizas M, Saltiel AR, LeRoith D. Insulin-like growth factor 1 inhibits apoptosis using the phosphatidylinositol 3’-kinase and mitogen-activated protein kinase pathways. J Biol Chem 1997; 272: 154–161.PubMedCrossRefGoogle Scholar
  63. 63.
    Wang L, Ma W, Markovich R, Chen JW, Wang PH. Regulation of cardiomyocyte apoptotic signaling by insulin-like growth factor I. Circ Res 1998; 83: 516–522.PubMedCrossRefGoogle Scholar
  64. 64.
    Wahlander H, Isgaard J, Jennische E, Friberg P. Left ventricular insulin-like growth factor I increases in early renal hypertension. Hypertension 1992; 19: 25–32.PubMedCrossRefGoogle Scholar
  65. 65.
    Hanson MC, Fath KA, Alexander RW, Delafontaine P. Induction of cardiac insulin-like growth factor I gene expression in pressure overload hypertrophy. Am J Med Sci 1993; 306: 69–74.PubMedCrossRefGoogle Scholar
  66. 66.
    Donohue TJ, Dworkin LD, Lango MN, et al. Induction of myocardial insulin-like growth factor-I gene expression in left ventricular hypertrophy. Circulation 1994; 89: 799–809.PubMedCrossRefGoogle Scholar
  67. 67.
    Isgaard J, Wahlander H, Adams MA, Friberg P. Increased expression of growth hormone receptor mRNA and insulin-like growth factor-I mRNA in volume-overloaded hearts. Hypertension 1994; 23: 884–888.PubMedCrossRefGoogle Scholar
  68. 68.
    Donohue TJ, Dworkin LD, Ma J, Lango MN, Catanese VM. Antihypertensive agents that limit ventricular hypertrophy inhibit cardiac expression of insulin-like growth factor-I. J Invest Med 1997; 45: 584–591.Google Scholar
  69. 69.
    Brink M, Chrast J, Price SR, Mitch WE, Delafontaine P. Angiotensin II stimulates gene expression of cardiac insulin-like growth factor I and its receptor through effects on blood pressure and food intake. Hypertension 1999; 34: 1053–1059.PubMedCrossRefGoogle Scholar
  70. 70.
    Pauliks LB, Cole KE, Mergner WJ. Increased insulin-like growth factor-1 protein in human left ventricular hypertrophy. Exp Mol Pathol 1999; 66: 53–58.PubMedCrossRefGoogle Scholar
  71. 71.
    Serneri GG, Modesti PA, Boddi M, et al. Cardiac growth factors in human hypertrophy. Relations with myocardial contractility and wall stress. Circ Res 1999; 85: 57–67.PubMedCrossRefGoogle Scholar
  72. 72.
    Kawano H, Do YS, Kawano Y, et al. Angiotensin II has multiple profibrotic effects in human cardiac fibroblasts. Circulation 2000; 101: 1130–1137.PubMedCrossRefGoogle Scholar
  73. 73.
    Weber KT. Extracellular matrix remodeling in heart failure: a role for de novo angiotensin II generation. Circulation 1997; 96: 4065–4082.PubMedCrossRefGoogle Scholar
  74. 74.
    Schunkert H, Jackson B, Tang SS, et al. Distribution and functional significance of cardiac angiotensin converting enzyme in hypertrophied rat hearts. Circulation 1993; 87: 1328–1339.PubMedCrossRefGoogle Scholar
  75. 75.
    Cheng CP, Suzuki M, Ohte N, Ohno M, Wang ZM, Little WC. Altered ventricular and myocyte response to angiotensin II in pacing-induced heart failure. Circ Res 1996; 78: 880–892.PubMedCrossRefGoogle Scholar
  76. 76.
    Beltrami AP, Urbanek K, Kajstura J, et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 2001; 344: 1750–1757.PubMedCrossRefGoogle Scholar
  77. 77.
    Meier P, Finch A, Evan G. Apoptosis in development. Nature 2000; 407: 796–801.PubMedCrossRefGoogle Scholar
  78. 78.
    Krammer PH. CD95’s deadly mission in the immune system. Nature 2000; 407: 789–795.PubMedCrossRefGoogle Scholar
  79. 79.
    James TN. Apoptosis in cardiac disease. Am J Med 1999; 107: 606–620.PubMedCrossRefGoogle Scholar
  80. 80.
    Thornberry NA, LazebnikY. Caspases: enemies within. Science 1998; 281: 1312–1316.PubMedCrossRefGoogle Scholar
  81. 81.
    Adams JM, Cory S. Life-or-death decisions by the Bc1–2 protein family. Trends Biochem Sci 2001; 26: 61–66.PubMedCrossRefGoogle Scholar
  82. 82.
    Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998; 281: 1322–1326.PubMedCrossRefGoogle Scholar
  83. 83.
    Yin XM, Wang K, Gross A, et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 1999; 400: 886–891.PubMedCrossRefGoogle Scholar
  84. 84.
    Shimizu S, Narita M, Tsujimoto Y. Bc1–2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 1999; 399: 483–487.PubMedCrossRefGoogle Scholar
  85. 85.
    Rasper DM, Vaillancourt JP, Hadano S, et al. Cell death attenuation by `Usurpin’, a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex. Cell Death Differ 1998; 5: 271–288.PubMedCrossRefGoogle Scholar
  86. 86.
    Uren AG, Coulson EJ, Vaux DL. Conservation of baculovirus inhibitor of apoptosis repeat proteins (BIRPs) in viruses, nematodes, vertebrates and yeasts. Trends Biochem Sci 1998; 23: 159–162.PubMedCrossRefGoogle Scholar
  87. 87.
    Srinivasula SM, Hegde R, Saleh A, et al. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature 2001; 410: 112–116.PubMedCrossRefGoogle Scholar
  88. 88.
    Irmler M, Thome M, Hahne M, et al. Inhibition of death receptor signals by cellular FLIP. Nature 1997; 388: 190–195.PubMedCrossRefGoogle Scholar
  89. 89.
    Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 1996; 335: 1182–1189.PubMedCrossRefGoogle Scholar
  90. 90.
    Olivetti G, Abbi R, Quaini F, et al. Apoptosis in the failing human heart. N Engl J Med 1997; 336: 1131–1141.PubMedCrossRefGoogle Scholar
  91. 91.
    Rayment NB, Haven AJ, Madden B, et al. Myocyte loss in chronic heart failure. J Pathol 1999; 188: 213–219.PubMedCrossRefGoogle Scholar
  92. 92.
    Kavantzas NG, Lazaris AC, Agapitos EV, Nanas J, Davaris PS. Histological assessment of apoptotic cell death in cardiomyopathies. Pathology 2000; 32: 176–180.PubMedGoogle Scholar
  93. 93.
    Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki LM. Apoptosis in human acute myocardial infarction. Circulation 1997; 95: 320–323.PubMedCrossRefGoogle Scholar
  94. 94.
    Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 1994; 94: 1621–1628.PubMedCrossRefGoogle Scholar
  95. 95.
    Guerra S, Leri A, Wang X, et al. Myocyte death in the failing human heart is gender dependent. Circ Res 1999; 85: 856–866.PubMedCrossRefGoogle Scholar
  96. 96.
    Mallat Z, Tedgui A, Fontaliran F, Frank R, Durigon M, Fontaine G. Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N Engl J Med 1996; 335: 1190–1196.PubMedCrossRefGoogle Scholar
  97. 97.
    Haunstetter A, Izumo S. Apoptosis: basic mechanisms and implications for cardiovascular disease. Circ Res 1998; 82: 1111–1129.PubMedCrossRefGoogle Scholar
  98. 98.
    Kang PM, Izumo S. Apoptosis and heart failure: A critical review of the literature. Circ Res 2000; 86: 1107–1113.PubMedCrossRefGoogle Scholar
  99. 99.
    Kotlyar AA, Vered Z, Goldberg I, et al. Insulin-like growth factor I and II preserve myocardial structure in postinfarct swine. Heart 2001; 86: 693–700.PubMedCrossRefGoogle Scholar
  100. 100.
    MacLellan WR, Schneider MD. Death by design. Programmed cell death in cardiovascular biology and disease. Circ Res 1997; 81: 137–144.PubMedCrossRefGoogle Scholar
  101. 101.
    Diep QN, El Mabrouk M, Yue P, Schiffrin EL. Effect of AT(1) receptor blockade on cardiac apoptosis in angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol 2002; 282: H1635 - H1641.PubMedGoogle Scholar
  102. 102.
    De Angelis N, Fiordaliso F, Latini R, et al. Appraisal of the Role of Angiotensin II and Aldosterone in Ventricular Myocyte Apoptosis in Adult Normotensive Rat. J Mol Cell Cardiol 2002; 34: 1655–1665.PubMedCrossRefGoogle Scholar
  103. 103.
    Fiordaliso F, Li B, Latini R, et al. Myocyte death in streptozotocin-induced diabetes in rats in angiotensin II- dependent. Lab Invest 2000; 80: 513–527.PubMedCrossRefGoogle Scholar
  104. 104.
    Berry C, Hamilton CA, Brosnan MJ, et al. Investigation into the sources of superoxide in human blood vessels: angiotensin II increases superoxide production in human internal mammary arteries. Circulation 2000; 101: 2206–2212.PubMedCrossRefGoogle Scholar
  105. 105.
    Rajagopalan S, Kurz S, Munzel T, et al. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 1996; 97: 1916–1923.PubMedCrossRefGoogle Scholar
  106. 106.
    von Harsdorf R, Li PF, Dietz R. Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis. Circulation 1999; 99: 2934–2941.PubMedCrossRefGoogle Scholar
  107. 107.
    Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 1993; 75: 977–984.PubMedCrossRefGoogle Scholar
  108. 108.
    Pierzchalski P, Reiss K, Cheng W, et al. p53 Induces myocyte apoptosis via the activation of the renin-angiotensin system. Exp Cell Res 1997; 234: 57–65.PubMedCrossRefGoogle Scholar
  109. 109.
    Leri A, Liu Y, Li B, et al. Up-regulation of AT(1) and AT(2) receptors in postinfarcted hypertrophied myocytes and stretch-mediated apoptotic cell death. Am J Pathol 2000; 156: 1663–1672.PubMedCrossRefGoogle Scholar
  110. 110.
    Battler A, Hasdai D, Goldberg 1, et al. Exogenous insulin-like growth factor II enhances post-infarction regional myocardial function in swine. Eur Heart J 1995; 16: 1851–1859.PubMedGoogle Scholar
  111. 111.
    Buerke M, Murohara T, Skurk C, Nuss C, Tomaselli K, Lefer AM. Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion. Proc Natl Acad Sci USA 1995; 92: 8031–8035.PubMedCrossRefGoogle Scholar
  112. 112.
    Jin H, Yang R, Gillett N, Clark RG, Ko A, Paoni NF. Beneficial effects of growth hormone and insulin-like growth factor-1 in experimental heart failure in rats treated with chronic ACE inhibition. J Cardiovasc Pharmacol 1995; 26: 420–425.PubMedCrossRefGoogle Scholar
  113. 113.
    Fujio Y, Nguyen T, Wencker D, Kitsis RN, Walsh K. Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation 2000; 101: 660–667.PubMedCrossRefGoogle Scholar
  114. 114.
    Matsui T, Li L, del Monte F, et al. Adenoviral gene transfer of activated phosphatidylinositol 3’-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation 1999; 100: 2373–2379.PubMedCrossRefGoogle Scholar
  115. 115.
    Lee WL, Chen JW, Ting CT, et al. Insulin-like growth factor I improves cardiovascular function and suppresses apoptosis of cardiomyocytes in dilated cardiomyopathy. Endocrinology 1999; 140: 4831–4840.PubMedCrossRefGoogle Scholar
  116. 116.
    Li Q, Li B, Wang X, et al. Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. J Clin Invest 1997; 100: 1991–1999.PubMedCrossRefGoogle Scholar
  117. 117.
    Duerr RL, McKirnan MD, Gim RD, Clark RG, Chien KR, Ross J, Jr. Cardiovascular effects of insulin-like growth factor-1 and growth hormone in chronic left ventricular failure in the rat. Circulation 1996; 93: 2188–2196.PubMedCrossRefGoogle Scholar
  118. 118.
    Cittadini A, Stromer H, Katz SE, et al. Differential cardiac effects of growth hormone and insulin-like growth factor-1 in the rat. A combined in vivo and in vitro evaluation. Circulation 1996; 93: 800–809.PubMedCrossRefGoogle Scholar
  119. 119.
    Duerr RL, Huang S, Miraliakbar HR, Clark R, Chien KR, Ross J, Jr. Insulin-like growth factor-1 enhances ventricular hypertrophy and function during the onset of experimental cardiac failure. J Clin Invest 1995; 95: 619–627.PubMedCrossRefGoogle Scholar
  120. 120.
    Welch S, Plank D, Witt S, et al. Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. Circ Res 2002; 90: 641–648.PubMedCrossRefGoogle Scholar
  121. 121.
    Weber A, Pennise CR, Babcock GG, Fowler VM. Tropomodulin caps the pointed ends of actin filaments. J Cell Biol 1994; 127: 1627–1635.PubMedCrossRefGoogle Scholar
  122. 122.
    Didenko VV, Hornsby PJ. Presence of double-strand breaks with single-base 3’ overhangs in cells undergoing apoptosis but not necrosis. J Cell Biol 1996; 135: 1369–1376.PubMedCrossRefGoogle Scholar
  123. 123.
    Didenko VV, Tunstead JR, Hornsby PJ. Biotin-labeled hairpin oligonucleotides: probes to detect double-strand breaks in DNA in apoptotic cells. Am J Pathol 1998; 152: 897–902.PubMedGoogle Scholar
  124. 124.
    Donath MY, Zapf J, Eppenberger-Eberhardt M, Froesch ER, Eppenberger HM. Insulin-like growth factor I stimulates myofibril development and decreases smooth muscle alpha-actin of adult cardiomyocytes. Proc Natl Acad Sci USA 1994; 91: 1686–1690.PubMedCrossRefGoogle Scholar
  125. 125.
    Kajstura J, Fiordaliso F, Andreoli AM, et al. IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes 2001; 50: 1414–1424.PubMedCrossRefGoogle Scholar
  126. 126.
    Nitahara JA, Cheng W, Liu Y, et al. Intracellular calcium, DNase activity and myocyte apoptosis in aging Fischer 344 rats. J Mol Cell Cardiol 1998; 30: 519–535.PubMedCrossRefGoogle Scholar
  127. 127.
    Leri A, Liu Y, Wang X, et al. Overexpression of insulin-like growth factor-1 attenuates the myocyte renin-angiotensin system in transgenic mice. Circ Res 1999; 84: 752–762.PubMedCrossRefGoogle Scholar
  128. 128.
    Redaelli G, Malhotra A, Li B, et al. Effects of constitutive overexpression of insulin-like growth factor-1 on the mechanical characteristics and molecular properties of ventricular myocytes. Circ Res 1998; 82: 594–603.PubMedCrossRefGoogle Scholar
  129. 129.
    Reiss K, Cheng W, Ferber A, et al. Overexpression of insulin-like growth factor-1 in the heart is coupled with myocyte proliferation in transgenic mice. Proc Natl Acad Sci USA 1996; 93: 8630–8635.PubMedCrossRefGoogle Scholar
  130. 130.
    Lee WL, Chen JW, Ting CT, Lin SJ, Wang PH. Changes of the insulin-like growth factor I system during acute myocardial infarction: implications on left ventricular remodeling. J Clin Endocrinol Metab 1999; 84: 1575–1581.PubMedCrossRefGoogle Scholar
  131. 131.
    Merola B, Cittadini A, Colao A, et al. Cardiac structural and functional abnormalities in adult patients with growth hormone deficiency. J Clin Endocrinol Metab 1993; 77: 1658–1661.PubMedCrossRefGoogle Scholar
  132. 132.
    Amato G, Carella C, Fazio S, et al. Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab 1993; 77: 1671–1676.PubMedCrossRefGoogle Scholar
  133. 133.
    Anversa P, Nadal-Ginard B. Myocyte renewal and ventricular remodelling. Nature 2002; 415: 240–243.PubMedCrossRefGoogle Scholar
  134. 134.
    Donath MY, Jenni R, Brunner HP, et al. Cardiovascular and metabolic effects of insulin-like growth factor I at rest and during exercise in humans. J Clin Endocrinol Metab 1996; 81: 4089–4094.PubMedCrossRefGoogle Scholar
  135. 135.
    Donath MY, Sutsch G, Yan XW, et al. Acute cardiovascular effects of insulin-like growth factor I in patients with chronic heart failure. J Clin Endocrinol Metab 1998; 83: 3177–3183.PubMedCrossRefGoogle Scholar
  136. 136.
    Perrot A, Ranke MB, Dietz R, Osterziel KJ. Growth hormone treatment in dilated cardiomyopathy. J Card Surg 2001; 16: 127–131.PubMedCrossRefGoogle Scholar
  137. 137.
    Anker SD, Volterrani M, Pflaum CD, et al. Acquired growth hormone resistance in patients with chronic heart failure: implications for therapy with growth hormone. J Am Coll Cardiol 2001; 38: 443–452.PubMedCrossRefGoogle Scholar
  138. 138.
    Ross J, Jr., Ryoke T. Effects of growth hormone and insulin-like growth factor I in experimental heart failure. Growth Horm IGF Res 1998; 8 (Suppl B): 159–161.PubMedCrossRefGoogle Scholar
  139. 139.
    Isgaard J, Bergh CH, Caidahl K, Lomsky M, Hjalmarson A, Bengtsson BA. A placebo-controlled study of growth hormone in patients with congestive heart failure. Eur Heart J 1998; 19: 1704–1711.PubMedCrossRefGoogle Scholar
  140. 140.
    Osterziel KJ, Strohm O, Schuler J, et al. Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet 1998; 351: 1233–1237.PubMedCrossRefGoogle Scholar
  141. 141.
    Baserga R. The IGF-I receptor in cancer research. Exp Cell Res 1999; 253: 1–6.PubMedCrossRefGoogle Scholar
  142. 142.
    Ma J, Pollak MN, Giovannucci E, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 1999; 91: 620–625.PubMedCrossRefGoogle Scholar
  143. 143.
    Wu Y, Yakar S, Zhao L, Hennighausen L, LeRoith D. Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res 2002; 62: 1030–1035.PubMedGoogle Scholar
  144. 144.
    Smith LE, Shen W, Perruzzi C, Soker S, Kinose F, Xu X, et al. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med 1999; 5: 1390–1395.PubMedCrossRefGoogle Scholar
  145. 145.
    Jabri N, Schalch DS, Schwartz SL, et al. Adverse effects of recombinant human insulin-like growth factor I in obese insulin-resistant type II diabetic patients. Diabetes 1994; 43: 369–374.PubMedCrossRefGoogle Scholar
  146. 146.
    Acerini CL, Patton CM, Savage MO, Kernel’ A, Westphal O, Dunger DB. Randomised placebo-controlled trial of human recombinant insulin-like growth factor I plus intensive insulin therapy in adolescents with insulin-dependent diabetes mellitus. Lancet 1997; 350: 1199–1204.PubMedCrossRefGoogle Scholar
  147. 147.
    Alila H, Coleman M, Nitta H, et al. Expression of biologically active human insulin-like growth factor-I following intramuscular injection of a formulated plasmid in rats. Hum Gene Ther 1997; 8: 1785–1795.PubMedCrossRefGoogle Scholar
  148. 148.
    Jeschke MG, Barrow RE, Hawkins HK, et al. IGF-I gene transfer in thermally injured rats. Gene Ther 1999; 6: 1015–1020.PubMedCrossRefGoogle Scholar
  149. 149.
    Su EJ, Cioffi CL, Stefansson S, Mittereder N, Garay M, Hreniuk D, et al. Gene therapy vector-mediated expression of insulin-like growth factors protects cardiomyocytes from apoptosis and enhances neovascularization. Am J Physiol Heart Circ Physiol 2002; 284: H1429 - H1440.PubMedGoogle Scholar
  150. 150.
    Adams TE, Epa VC, Garrett TP, Ward CW. Structure and function of the type 1 insulin-like growth factor receptor. Cell Mol Life Sci 2000; 57: 1050–1093.PubMedCrossRefGoogle Scholar
  151. 151.
    White MF. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem 1998; 182: 3–11.PubMedCrossRefGoogle Scholar
  152. 152.
    White MF, Kahn CR. The insulin signaling system. J Biol Chem 1994; 269: 1–4.PubMedGoogle Scholar
  153. 153.
    Dhand R, Hara K, Hiles I, et al. PI 3-kinase: structural and functional analysis of intersubunit interactions. Embo J 1994; 13: 511–521.PubMedGoogle Scholar
  154. 154.
    Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91: 231–241.PubMedCrossRefGoogle Scholar
  155. 155.
    Cardone MH, Roy N, Stennicke HR, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998; 282: 1318–1321.PubMedCrossRefGoogle Scholar
  156. 156.
    Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999; 96: 857–868.PubMedCrossRefGoogle Scholar
  157. 157.
    Condorelli G, Drusco A, Stassi G, et al. Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci USA 2002; 99: 12333–12338.PubMedCrossRefGoogle Scholar
  158. 158.
    Matsui T, Tao J, del Monte F, et al. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 2001; 104: 330–335.PubMedCrossRefGoogle Scholar
  159. 159.
    Yamashita K, Kajstura J, Discher DJ, et al. Reperfusion-activated Akt kinase prevents apoptosis in transgenic mouse hearts overexpressing insulin-like growth factor-l. Circ Res 2001; 88: 609–614.PubMedCrossRefGoogle Scholar
  160. 160.
    Wu W, Lee WL, Wu YY, et al. Expression of constitutively active phosphatidylinositol 3-kinase inhibits activation of caspase 3 and apoptosis of cardiac muscle cells. J Biol Chem 2000; 275: 40113–40119.PubMedCrossRefGoogle Scholar
  161. 161.
    Mehrhof FB, Muller FU, Bergmann MW, et al. In cardiomyocyte hypoxia, insulin-like growth factorI-induced antiapoptotic signaling requires phosphatidylinositol-3-OH-kinase-dependent and mitogen-activated protein kinase-dependent activation of the transcription factor cAMP response element-binding protein. Circulation 2001; 104: 2088–2094.PubMedCrossRefGoogle Scholar
  162. 162.
    Anker SD, Ponikowski P, Varney S, et al. Wasting as independent risk factor for mortality in chronic heart failure. Lancet 1997; 349: 1050–1053.PubMedCrossRefGoogle Scholar
  163. 163.
    Fink LI, Wilson JR, Ferraro N. Exercise ventilation and pulmonary artery wedge pressure in chronic stable congestive heart failure. Am J Cardiol 1986; 57: 249–253.PubMedCrossRefGoogle Scholar
  164. 164.
    Sullivan MJ, Knight JD, Higginbotham MB, Cobb FR. Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure. Muscle blood flow is reduced with maintenance of arterial perfusion pressure. Circulation 1989; 80: 769–781.PubMedCrossRefGoogle Scholar
  165. 165.
    Wilson JR, Martin JL, Schwartz D, Ferraro N. Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle. Circulation 1984; 69: 1079–1087.PubMedCrossRefGoogle Scholar
  166. 166.
    Minotti JR, Pillay P, Oka R, Wells L, Christoph I, Massie BM. Skeletal muscle size: relationship to muscle function in heart failure. J Appl Physiol 1993; 75: 373–381.PubMedGoogle Scholar
  167. 167.
    Mancini DM, Walter G, Reichek N, et al. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation 1992; 85: 1364–1373.PubMedCrossRefGoogle Scholar
  168. 168.
    Hambrecht R, Schulze PC, Gielen S, et al. Reduction of insulin-like growth factor-I expression in the skeletal muscle of noncachectic patients with chronic heart failure. J Am Coll Cardiol 2002; 39: 1175–1181.PubMedCrossRefGoogle Scholar
  169. 169.
    McMurray J, Abdullah I, Dargie HJ, Shapiro D. Increased concentrations of tumour necrosis factor in “cachectic” patients with severe chronic heart failure. Br Heart J 1991; 66: 356–358.PubMedCrossRefGoogle Scholar
  170. 170.
    Cicoira M, Bolger AP, Doehner W, et al. High tumour necrosis factor-alpha levels are associated with exercise intolerance and neurohormonal activation in chronic heart failure patients. Cytokine 2001; 15: 80–86.PubMedCrossRefGoogle Scholar
  171. 171.
    Krown KA, Page MT, Nguyen C, et al. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest 1996; 98: 2854–2865.PubMedCrossRefGoogle Scholar
  172. 172.
    Vescovo G, Volterrani M, Zennaro R, et al. Apoptosis in the skeletal muscle of patients with heart failure: investigation of clinical and biochemical changes. Heart 2000; 84: 431–437.PubMedCrossRefGoogle Scholar
  173. 173.
    Adams V, Jiang H, Yu J, et al. Apoptosis in skeletal myocytes of patients with chronic heart failure is associated with exercise intolerance. J Am Coll Cardiol 1999; 33: 959–965.PubMedCrossRefGoogle Scholar
  174. 174.
    Hambrecht R, Adams V, Gielen S, et al. Exercise intolerance in patients with chronic heart failure and increased expression of inducible nitric oxide synthase in the skeletal muscle. J Am Coll Cardiol 1999; 33: 174–179.PubMedCrossRefGoogle Scholar
  175. 175.
    Vescovo G, Zennaro R, Sandri M, et al. Apoptosis of skeletal muscle myofibers and interstitial cells in experimental heart failure. J Mol Cell Cardiol 1998; 30: 2449–2459.PubMedCrossRefGoogle Scholar
  176. 176.
    Brink M, Wellen J, Delafontaine P. Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism. J Clin Invest 1996; 97: 2509–2516.PubMedCrossRefGoogle Scholar
  177. 177.
    Brink M, Price SR, Chrast J, et al. Angiotensin II induces skeletal muscle wasting through enhanced protein degradation and down-regulates autocrine insulin-like growth factor I. Endocrinology 2001; 142: 1489–1496.PubMedCrossRefGoogle Scholar
  178. 178.
    Linderman JR, Greene AS. Distribution of angiotensin II receptor expression in the microcirculation of striated muscle. Microcirculation 2001; 8: 275–281.PubMedGoogle Scholar
  179. Brink M, Anwar A, Delafontaine P. Neurohormonal factors in the development of catabolic/anabolic imbalance and cachexia. Int J Cardiol 2002;85:111–121, discussion 121–124.Google Scholar
  180. 180.
    Anwar A, Gaspoz JM, Pampallona S, et al. Effect of congestive heart failure on the insulin-like growth factor-1 system. Am J Cardiol 2002; 90: 1402–1405.PubMedCrossRefGoogle Scholar
  181. 181.
    Corbalan R, Acevedo M, Godoy I, Jalil J, Campusano C, Klassen J. Enalapril restores depressed circulating insulin-like growth factor 1 in patients with chronic heart failure. J Card Fail 1998; 4: 115–119.PubMedCrossRefGoogle Scholar
  182. 182.
    Broglio F, Fubini A, Morello M, et al. Activity of GH/IGF-I axis in patients with dilated cardiomyopathy. Clin Endocrinol (Oxf) 1999; 50: 417–430.CrossRefGoogle Scholar
  183. 183.
    Osterziel KJ, Ranke MB, Strohm O, Dietz R. The somatotrophic system in patients with dilated cardiomyopathy: relation of insulin-like growth factor-1 and its alterations during growth hormone therapy to cardiac function. Clin Endocrinol (Oxf) 2000; 53: 61–68.CrossRefGoogle Scholar
  184. 184.
    Cittadini A, Grossman JD, Stromer H, Katz SE, Morgan JP, Douglas PS. Importance of an intact growth hormone/insulin-like growth factor 1 axis for normal post-infarction healing: studies in dwarf rats. Endocrinology 2001; 142: 332–338.PubMedCrossRefGoogle Scholar
  185. 185.
    Al-Obaidi MK, Hon JK, Stubbs PJ, et al. Plasma insulin-like growth factor-1 elevated in mild-tomoderate but not severe heart failure. Am Heart J 2001; 142: E10.PubMedCrossRefGoogle Scholar
  186. 186.
    Miyashita T, Krajewski S, Krajewska M, et al. Tumor suppressor p53 is a regulator of bc1–2 and bax gene expression in vitro and in vivo. Oncogene 1994; 9: 1799–1805.PubMedGoogle Scholar
  187. 187.
    Reed JC. Bc1–2 and the regulation of programmed cell death. J Cell Biol 1994; 124: 1–6.PubMedCrossRefGoogle Scholar
  188. 188.
    Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995; 80: 293–299.PubMedCrossRefGoogle Scholar
  189. 189.
    Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev 1993; 7: 1126–1132.PubMedCrossRefGoogle Scholar
  190. 190.
    Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature 1997; 387: 296–299.PubMedCrossRefGoogle Scholar
  191. 191.
    Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature 1997; 387: 299–303.PubMedCrossRefGoogle Scholar
  192. 192.
    Folli F, Kahn CR, Hansen H, Bouchie JL, Feener EP. Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels. A potential role for serine phosphorylation in insulin/angiotensin II crosstalk. J Clin Invest 1997; 100: 2158–2169.PubMedCrossRefGoogle Scholar
  193. 193.
    Folli F, Saad MJ, Velloso L, et al. Crosstalk between insulin and angiotensin II signalling systems. Exp Clin Endocrinol Diabetes 1999; 107: 133–139.PubMedCrossRefGoogle Scholar
  194. 194.
    Barton-Davis ER, Shoturma DI, Musaro A, Rosenthal N, Sweeney HL. Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function. Proc Natl Acad Sci U S A 1998; 95: 15603–15607.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Patrice Delafontaine
  • Marijke Brink
  • Yao-Hua Song

There are no affiliations available

Personalised recommendations