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The rationale for cardiomyocyte resuscitation in myocardial salvage

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Abstract

Clinical heart failure results from the cumulative loss of functioning myocardium from any cause. At the cellular level, cardiac myocytes die from three causes, individually or in combination: Necrosis occurs when external conditions are not sufficient to sustain minimal cellular functions, as with ischemia, and there is a general and unorganized breakdown of cell organelles, engendering an inflammatory response that may have harmful collateral tissue effects. Apoptosis, or cell suicide, occurs when specific external or internal conditions provoke a highly structured sequence of events to shut down cellular functions and remove the cell, with minimal consequences to surrounding tissue. Autophagy is a normal response to cell starvation that is induced under conditions of chronic metabolic or other stress. Current therapeutics, such as early myocardial revascularization after myocardial infarction, are focused exclusively upon minimizing cardiac myocyte necrosis and may even contribute to secondary apoptosis and autophagy. This review explores possible approaches to bring cardiac myocytes that are destined to die, back to life, i.e., cellular resuscitation. Two pro-apoptotic proteins in particular, Bnip3 and Nix, are transcriptionally upregulated specifically in response to myocardial ischemia and pathological hypertrophy and have been examined as therapeutic targets. In Bnip3 and Nix genetic mouse models, prevention of cardiac myocyte apoptosis in ischemic and hemodynamically overloaded hearts salvaged myocardium, minimized late ventricular remodeling, and enhanced ventricular performance. Cardiomyocyte resuscitation by preventing programmed cell death shows promise as an additive approach to minimizing necrosis for long-term prevention of heart failure.

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References

  1. Kacimi R, Chentoufi J, Honbo N, Long CS, Karliner JS (2000) Hypoxia differentially regulates stress proteins in cultured cardiomyocytes: role of the p38 stress-activated kinase signaling cascade, and relation to cytoprotection. Cardiovasc Res 46:139–150

    Article  PubMed  CAS  Google Scholar 

  2. Ohata H, Trollinger DR, Lemasters JJ (1994) Changes in shape and viability of cultured adult rabbit cardiac myocytes during ischemia/reperfusion injury. Res Commun Mol Pathol Pharmacol 86:259–271

    PubMed  CAS  Google Scholar 

  3. Tanaka M, Ito H, Adachi S, Akimoto H, Nishikawa T, Kasajima T, Marumo F, Hiroe M (1994) Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes. Circ Res 75:426–433

    PubMed  CAS  Google Scholar 

  4. Umansky SR, Shapiro JP, Cuenco GM, Foehr MW, Bathurst IC, Tomei LD (1997) Prevention of rat neonatal cardiomyocyte apoptosis induced by simulated in vitro ischemia and reperfusion. Cell Death Differ 4:608–616

    Article  PubMed  CAS  Google Scholar 

  5. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O’Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y, American Heart Association Statistics Committee and Stroke Statistics Subcommittee (2008) Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 117(4):e25–e146

    Article  PubMed  Google Scholar 

  6. Zheng ZJ, Croft JB, Giles WH, Mensah GA (2001) Sudden cardiac death in the United States, 1989 to 1998. Circulation 104:2158–2163

    Article  PubMed  CAS  Google Scholar 

  7. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK (1996) The progression from hypertension to congestive heart failure. JAMA 275:1557–1562

    Article  PubMed  CAS  Google Scholar 

  8. Berry JJ, Hoffman JM, Steenbergen C, Baker JA, Floyd C, Van Trigt P, Hanson MW, Coleman RE (1993) Human pathologic correlation with PET in ischemic and nonischemic cardiomyopathy. J Nucl Med 34:39–47

    PubMed  CAS  Google Scholar 

  9. Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA, Quaini E, Di Loreto C, Beltrami CA, Krajewski S, Reed JC, Anversa P (1997) Apoptosis in the failing human heart. N Engl J Med 336:1131–1141

    Article  PubMed  CAS  Google Scholar 

  10. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B (2005) ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing committee to update the 2001 guidelines for the evaluation and management of heart failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 112:e154–e235

    Article  PubMed  Google Scholar 

  11. St John SM, Pfeffer MA, Moye L, Plappert T, Rouleau JL, Lamas G, Rouleau J, Parker JO, Arnold MO, Sussex B, Braunwald E (1997) Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation 96:3294–3299

    Google Scholar 

  12. Pfeffer MA, Braunwald E (1990) Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 81:1161–1172

    PubMed  CAS  Google Scholar 

  13. Jackson BM, Gorman JH III, Salgo IS, Moainie SL, Plappert T, John-Sutton M, Edmunds LH Jr, Gorman RC (2003) Border zone geometry increases wall stress after myocardial infarction: contrast echocardiographic assessment. Am J Physiol Heart Circ Physiol 284:H475–H479

    PubMed  CAS  Google Scholar 

  14. Grossman W, Jones D, McLaurin LP (1975) Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 56:56–64

    Article  PubMed  CAS  Google Scholar 

  15. Fieno DS, Hillenbrand HB, Rehwald WG, Harris KR, Decker RS, Parker MA, Klocke FJ, Kim RJ, Judd RM (2004) Infarct resorption, compensatory hypertrophy, and differing patterns of ventricular remodeling following myocardial infarctions of varying size. J Am Coll Cardiol 43:2124–2131

    Article  PubMed  Google Scholar 

  16. Shioura KM, Geenen DL, Goldspink PH (2007) Assessment of cardiac function with the pressure–volume conductance system following myocardial infarction in mice. Am J Physiol Heart Circ Physiol 293:H2870–H2877

    Article  PubMed  CAS  Google Scholar 

  17. Setser R, Henson RE, Allen JS, Fischer SE, Wickline SA, Loren CH (2000) Left ventricular contractility is impaired following myocardial infarction in the pig and rat: assessment by the end systolic pressure–volume relation using a single-beat estimation technique and cine magnetic resonance imaging. Ann Biomed Eng 28:484–494

    Article  PubMed  CAS  Google Scholar 

  18. Sun Y, Kiani MF, Postlethwaite AE, Weber KT (2002) Infarct scar as living tissue. Basic Res Cardiol 97:343–347

    Article  PubMed  Google Scholar 

  19. Jackson BM, Gorman JH, Moainie SL, Guy TS, Narula N, Narula J, John-Sutton MG, Edmunds LH Jr, Gorman RC (2002) Extension of borderzone myocardium in postinfarction dilated cardiomyopathy. J Am Coll Cardiol 40:1160–1167

    Article  PubMed  Google Scholar 

  20. Frey N, Katus HA, Olson EN, Hill JA (2004) Hypertrophy of the heart: a new therapeutic target? Circulation 109:1580–1589

    Article  PubMed  Google Scholar 

  21. Diwan A, Dorn GW (2007) Decompensation of cardiac hypertrophy: cellular mechanisms and novel therapeutic targets. Physiology 22:56–64

    Article  PubMed  CAS  Google Scholar 

  22. Esposito G, Rapacciuolo A, Naga Prasad SV, Takaoka H, Thomas SA, Koch WJ, Rockman HA (2002) Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress. Circulation 105:85–92

    Article  PubMed  CAS  Google Scholar 

  23. van Rooij E, Doevendans PA, Crijns HJ, Heeneman S, Lips DJ, van Bilsen M, Williams RS, Olson EN, Bassel-Duby R, Rothermel BA, De Windt LJ (2004) MCIP1 overexpression suppresses left ventricular remodeling and sustains cardiac function after myocardial infarction. Circ Res 94:e18–e26

    Article  PubMed  CAS  Google Scholar 

  24. Hill JA, Karimi M, Kutschke W, Davisson RL, Zimmerman K, Wang Z, Kerber RE, Weiss RM (2000) Cardiac hypertrophy is not a required compensatory response to short-term pressure overload. Circulation 101:2863–2869

    PubMed  CAS  Google Scholar 

  25. Hill JA, Rothermel B, Yoo KD, Cabuay B, Demetroulis E, Weiss RM, Kutschke W, Bassel-Duby R, Williams RS (2002) Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function. J Biol Chem 277:10251–10255

    Article  PubMed  CAS  Google Scholar 

  26. Sano M, Schneider MD (2002) Still stressed out but doing fine: normalization of wall stress is superfluous to maintaining cardiac function in chronic pressure overload. Circulation 105:8–10

    PubMed  Google Scholar 

  27. Foo RS, Mani K, Kitsis RN (2005) Death begets failure in the heart. J Clin Invest 115:565–571

    Article  PubMed  CAS  Google Scholar 

  28. Olivetti G, Capasso JM, Sonnenblick EH, Anversa P (1990) Side-to-side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats. Circ Res 67:23–34

    PubMed  CAS  Google Scholar 

  29. Abbate A, Bussani R, Biondi-Zoccai GG, Santini D, Petrolini A, De Giorgio F, Vasaturo F, Scarpa S, Severino A, Liuzzo G, Leone AM, Baldi F, Sinagra G, Silvestri F, Vetrovec GW, Crea F, Biasucci LM, Baldi A (2005) Infarct-related artery occlusion, tissue markers of ischaemia, and increased apoptosis in the peri-infarct viable myocardium. Eur Heart J 26:2039–2045

    Article  PubMed  CAS  Google Scholar 

  30. Cheng W, Kajstura J, Nitahara JA, Li B, Reiss K, Liu Y, Clark WA, Krajewski S, Reed JC, Olivetti G, Anversa P (1996) Programmed myocyte cell death affects the viable myocardium after infarction in rats. Exp Cell Res 226:316–327

    Article  PubMed  CAS  Google Scholar 

  31. Itoh G, Tamura J, Suzuki M, Suzuki Y, Ikeda H, Koike M, Nomura M, Jie T, Ito K (1995) DNA fragmentation of human infarcted myocardial cells demonstrated by the nick end labeling method and DNA agarose gel electrophoresis. Am J Pathol 146:1325–1331

    PubMed  CAS  Google Scholar 

  32. Kajstura J, Cheng W, Reiss K, Clark WA, Sonnenblick EH, Krajewski S, Reed JC, Olivetti G, Anversa P (1996) Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest 74:86–107

    PubMed  CAS  Google Scholar 

  33. Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki LM (1997) Apoptosis in human acute myocardial infarction. Circulation 95:320–323

    PubMed  CAS  Google Scholar 

  34. Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL (1994) Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 94:1621–1628

    Article  PubMed  CAS  Google Scholar 

  35. Depre C, Kim SJ, John AS, Huang Y, Rimoldi OE, Pepper JR, Dreyfus GD, Gaussin V, Pennell DJ, Vatner DE, Camici PG, Vatner SF (2004) Program of cell survival underlying human and experimental hibernating myocardium. Circ Res 95:433–440

    Article  PubMed  CAS  Google Scholar 

  36. Elsasser A, Vogt AM, Nef H, Kostin S, Mollmann H, Skwara W, Bode C, Hamm C, Schaper J (2004) Human hibernating myocardium is jeopardized by apoptotic and autophagic cell death. J Am Coll Cardiol 43:2191–2199

    Article  PubMed  Google Scholar 

  37. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J (2007) Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 100:914–922

    Article  PubMed  CAS  Google Scholar 

  38. Bialik S, Geenen DL, Sasson IE, Cheng R, Horner JW, Evans SM, Lord EM, Koch CJ, Kitsis RN (1997) Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53. J Clin Invest 100:1363–1372

    Article  PubMed  CAS  Google Scholar 

  39. Dellborg M, Held P, Swedberg K, Vedin A (1985) Rupture of the myocardium. Occurrence and risk factors. Br Heart J 54:11–16

    Article  PubMed  CAS  Google Scholar 

  40. Entman ML, Smith CW (1994) Postreperfusion inflammation: a model for reaction to injury in cardiovascular disease. Cardiovasc Res 28:1301–1311

    Article  PubMed  CAS  Google Scholar 

  41. Matsumura K, Jeremy RW, Schaper J, Becker LC (1998) Progression of myocardial necrosis during reperfusion of ischemic myocardium. Circulation 97:795–804

    PubMed  CAS  Google Scholar 

  42. Fliss H, Gattinger D (1996) Apoptosis in ischemic and reperfused rat myocardium. Circ Res 79:949–956

    PubMed  CAS  Google Scholar 

  43. Sam F, Sawyer DB, Chang DL, Eberli FR, Ngoy S, Jain M, Amin J, Apstein CS, Colucci WS (2000) Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart. Am J Physiol Heart Circ Physiol 279:H422–H428

    PubMed  CAS  Google Scholar 

  44. Mann DL, Bristow MR (2005) Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation 111:2837–2849

    Article  PubMed  Google Scholar 

  45. Hein S, Arnon E, Kostin S, Schonburg M, Elsasser A, Polyakova V, Bauer EP, Klovekorn WP, Schaper J (2003) Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation 107:984–991

    Article  PubMed  Google Scholar 

  46. Adams JW, Sakata Y, Davis MG, Sah VP, Wang Y, Liggett SB, Chien KR, Brown JH, Dorn GW (1998) Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad Sci U S A 95:10140–10145

    Article  PubMed  CAS  Google Scholar 

  47. D’Angelo DD, Sakata Y, Lorenz JN, Boivin GP, Walsh RA, Liggett SB, Dorn GW (1997) Transgenic Galphaq overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci U S A 94:8121–8126

    Article  PubMed  CAS  Google Scholar 

  48. Sakata Y, Hoit BD, Liggett SB, Walsh RA, Dorn GW (1998) Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice. Circulation 97:1488–1495

    PubMed  CAS  Google Scholar 

  49. Vatner SF (1988) Reduced subendocardial myocardial perfusion as one mechanism for congestive heart failure. Am J Cardiol 62:94E–98E

    Article  PubMed  CAS  Google Scholar 

  50. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci WS, Walsh K (2005) Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 115:2108–2118

    Article  PubMed  CAS  Google Scholar 

  51. Spinale FG (2007) Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev 87:1285–1342

    Article  PubMed  CAS  Google Scholar 

  52. Ikeda S, Hamada M, Qu P, Hiasa G, Hashida H, Shigematsu Y, Hiwada K (2002) Relationship between cardiomyocyte cell death and cardiac function during hypertensive cardiac remodelling in Dahl rats. Clin Sci (Lond) 102:329–335

    Article  Google Scholar 

  53. Kim Y, Phan D, van Rooij E, Wang DZ, McAnally J, Qi X, Richardson JA, Hill JA, Bassel-Duby R, Olson EN (2008) The MEF2D transcription factor mediates stress-dependent cardiac remodeling in mice. J Clin Invest 118:124–132

    Article  PubMed  CAS  Google Scholar 

  54. Li Z, Bing OH, Long X, Robinson KG, Lakatta EG (1997) Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Physiol 272:H2313–H2319

    PubMed  CAS  Google Scholar 

  55. Sadoshima J, Montagne O, Wang Q, Yang G, Warden J, Liu J, Takagi G, Karoor V, Hong C, Johnson GL, Vatner DE, Vatner SF (2002) The MEKK1–JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy. J Clin Invest 110:271–279

    PubMed  CAS  Google Scholar 

  56. Teiger E, Than VD, Richard L, Wisnewsky C, Tea BS, Gaboury L, Tremblay J, Schwartz K, Hamet P (1996) Apoptosis in pressure overload-induced heart hypertrophy in the rat. J Clin Invest 97:2891–2897

    Article  PubMed  CAS  Google Scholar 

  57. Packer M (1995) Evolution of the neurohormonal hypothesis to explain the progression of chronic heart failure. Eur Heart J 16(Suppl F):4–6

    PubMed  CAS  Google Scholar 

  58. Dorn GW (2005) Physiologic growth and pathologic genes in cardiac development and cardiomyopathy. Trends Cardiovasc Med 15:185–189

    Article  PubMed  CAS  Google Scholar 

  59. Chandrashekhar Y, Sen S, Anway R, Shuros A, Anand I (2004) Long-term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and attenuates remodeling in rats with myocardial infarction. J Am Coll Cardiol 43:295–301

    Article  PubMed  CAS  Google Scholar 

  60. Yaoita H, Ogawa K, Maehara K, Maruyama Y (1998) Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation 97:276–281

    PubMed  CAS  Google Scholar 

  61. Hayakawa Y, Chandra M, Miao W, Shirani J, Brown JH, Dorn GW, Armstrong RC, Kitsis RN (2003) Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice. Circulation 108:3036–3041

    Article  PubMed  CAS  Google Scholar 

  62. Okamura T, Miura T, Takemura G, Fujiwara H, Iwamoto H, Kawamura S, Kimura M, Ikeda Y, Iwatate M, Matsuzaki M (2000) Effect of caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation in the ischemia-reperfused rat heart. Cardiovasc Res 45:642–650

    Article  PubMed  CAS  Google Scholar 

  63. Crow MT, Mani K, Nam YJ, Kitsis RN (2004) The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res 95:957–970

    Article  PubMed  CAS  Google Scholar 

  64. Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219

    Article  PubMed  CAS  Google Scholar 

  65. Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59

    Article  PubMed  CAS  Google Scholar 

  66. Strasser A (2005) The role of BH3-only proteins in the immune system. Nat Rev Immunol 5:189–200

    Article  PubMed  CAS  Google Scholar 

  67. Brocheriou V, Hagege AA, Oubenaissa A, Lambert M, Mallet VO, Duriez M, Wassef M, Kahn A, Menasche P, Gilgenkrantz H (2000) Cardiac functional improvement by a human Bcl-2 transgene in a mouse model of ischemia/reperfusion injury. J Gene Med 2:326–333

    Article  PubMed  CAS  Google Scholar 

  68. Chen Z, Chua CC, Ho YS, Hamdy RC, Chua BH (2001) Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. Am J Physiol Heart Circ Physiol 280:H2313–H2320

    PubMed  CAS  Google Scholar 

  69. Imahashi K, Schneider MD, Steenbergen C, Murphy E (2004) Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury. Circ Res 95:734–741

    Article  PubMed  CAS  Google Scholar 

  70. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927–939

    Article  PubMed  CAS  Google Scholar 

  71. Gustafsson AB, Sayen MR, Williams SD, Crow MT, Gottlieb RA (2002) TAT protein transduction into isolated perfused hearts: TAT-apoptosis repressor with caspase recruitment domain is cardioprotective. Circulation 106:735–739

    PubMed  CAS  Google Scholar 

  72. Donath S, Li P, Willenbockel C, Al Saadi N, Gross V, Willnow T, Bader M, Martin U, Bauersachs J, Wollert KC, Dietz R, von Harsdorf R (2006) Apoptosis repressor with caspase recruitment domain is required for cardioprotection in response to biomechanical and ischemic stress. Circulation 113:1203–1212

    Article  PubMed  CAS  Google Scholar 

  73. Hochhauser E, Kivity S, Offen D, Maulik N, Otani H, Barhum Y, Pannet H, Shneyvays V, Shainberg A, Goldshtaub V, Tobar A, Vidne BA (2003) Bax ablation protects against myocardial ischemia–reperfusion injury in transgenic mice. Am J Physiol Heart Circ Physiol 284:H2351–H2359

    PubMed  CAS  Google Scholar 

  74. Hochhauser E, Cheporko Y, Yasovich N, Pinchas L, Offen D, Barhum Y, Pannet H, Tobar A, Vidne BA, Birk E (2007) Bax deficiency reduces infarct size and improves long-term function after myocardial infarction. Cell Biochem Biophys 47:11–20

    PubMed  CAS  Google Scholar 

  75. Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, Frauwirth K, Chen Y, Wei M, Eng VM, Adelman DM, Simon MC, Ma A, Golden JA, Evan G, Korsmeyer SJ, MacGregor GR, Thompson CB (2000) The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6:1389–1399

    Article  PubMed  CAS  Google Scholar 

  76. Moller C, Karlberg M, Abrink M, Nakayama KI, Motoyama N, Nilsson G (2007) Bcl-2 and Bcl-XL are indispensable for the late phase of mast cell development from mouse embryonic stem cells. Exp Hematol 35:385–393

    Article  PubMed  CAS  Google Scholar 

  77. Boyd JM, Malstrom S, Subramanian T, Venkatesh LK, Schaeper U, Elangovan B, D'Sa-Eipper C, Chinnadurai G (1994) Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. Cell 79:341–351

    Article  PubMed  CAS  Google Scholar 

  78. Chen G, Cizeau J, Vande VC, Park JH, Bozek G, Bolton J, Shi L, Dubik D, Greenberg A (1999) Nix and Nip3 form a subfamily of pro-apoptotic mitochondrial proteins. J Biol Chem 274:7–10

    Article  PubMed  CAS  Google Scholar 

  79. Diwan A, Wansapura J, Syed FM, Matkovich SJ, Lorenz JN, Dorn GW (2008) Nix-mediated apoptosis links myocardial fibrosis, cardiac remodeling, and hypertrophy decompensation. Circulation 117:396–404

    Article  PubMed  CAS  Google Scholar 

  80. Galvez AS, Brunskill EW, Marreez Y, Benner BJ, Regula KM, Kirschenbaum LA, Dorn GW (2006) Distinct pathways regulate proapoptotic Nix and BNip3 in cardiac stress. J Biol Chem 281:1442–1448

    Article  PubMed  CAS  Google Scholar 

  81. Yasuda M, Theodorakis P, Subramanian T, Chinnadurai G (1998) Adenovirus E1B-19K/BCL-2 interacting protein BNIP3 contains a BH3 domain and a mitochondrial targeting sequence. J Biol Chem 273:12415–12421

    Article  PubMed  CAS  Google Scholar 

  82. Diwan A, Koesters AG, Odley AM, Pushkaran S, Baines CP, Spike BT, Daria D, Jegga AG, Geiger H, Aronow BJ, Molkentin JD, Macleod KF, Kalfa TA, Dorn GW (2007) Unrestrained erythroblast development in Nix−/− mice reveals a mechanism for apoptotic modulation of erythropoiesis. Proc Natl Acad Sci U S A 104:6794–6799

    Article  PubMed  CAS  Google Scholar 

  83. Kubli DA, Ycaza JE, Gustafsson AB (2007) Bnip3 mediates mitochondrial dysfunction and cell death through Bax and Bak. Biochem J 405(3):407–15 Aug 1

    Article  PubMed  CAS  Google Scholar 

  84. Yussman MG, Toyokawa T, Odley A, Lynch RA, Wu G, Colbert MC, Aronow BJ, Lorenz JN, Dorn GW (2002) Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nat Med 8:725–730

    PubMed  CAS  Google Scholar 

  85. Cizeau J, Ray R, Chen G, Gietz RD, Greenberg AH (2000) The C. elegans orthologue ceBNIP3 interacts with CED-9 and CED-3 but kills through a BH3- and caspase-independent mechanism. Oncogene 19:5453–5463

    Article  PubMed  CAS  Google Scholar 

  86. Diwan A, Krenz M, Syed FM, Wansapura J, Ren X, Koesters AG, Li H, Kirshenbaum LA, Hahn HS, Robbins J, Jones WK, Dorn GW (2007) Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice. J Clin Invest 117:2825–2833

    Article  PubMed  CAS  Google Scholar 

  87. Bruick RK (2000) Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc Natl Acad Sci U S A 97:9082–9087

    Article  PubMed  CAS  Google Scholar 

  88. Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, Gottlieb RA, Gustafsson AB (2007) Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ 14:146–157

    Article  PubMed  CAS  Google Scholar 

  89. Kubasiak LA, Hernandez OM, Bishopric NH, Webster KA (2002) Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. Proc Natl Acad Sci U S A 99:12825–12830

    Article  PubMed  CAS  Google Scholar 

  90. Regula KM, Ens K, Kirshenbaum LA (2002) Inducible expression of BNIP3 provokes mitochondrial defects and hypoxia-mediated cell death of ventricular myocytes. Circ Res 91:226–231

    Article  PubMed  CAS  Google Scholar 

  91. Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL (2001) HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res 61:6669–6673

    PubMed  CAS  Google Scholar 

  92. Graham RM, Frazier DP, Thompson JW, Haliko S, Li H, Wasserlauf BJ, Spiga MG, Bishopric NH, Webster KA (2004) A unique pathway of cardiac myocyte death caused by hypoxia-acidosis. J Exp Biol 207:3189–3200

    Article  PubMed  CAS  Google Scholar 

  93. Aronow BJ, Toyokawa T, Canning A, Haghighi K, Delling U, Kranias E, Molkentin JD, Dorn GW (2001) Divergent transcriptional responses to independent genetic causes of cardiac hypertrophy. Physiol Genomics 6:19–28

    PubMed  CAS  Google Scholar 

  94. Syed F, Odley A, Hahn HS, Brunskill EW, Lynch RA, Marreez Y, Sanbe A, Robbins J, Dorn GW (2004) Physiological growth synergizes with pathological genes in experimental cardiomyopathy. Circ Res 95:1200–1206

    Article  PubMed  CAS  Google Scholar 

  95. Vande VC, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S, Hakem R, Greenberg AH (2000) BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol Cell Biol 20:5454–5468

    Article  Google Scholar 

  96. Kanzawa T, Zhang L, Xiao L, Germano IM, Kondo Y, Kondo S (2005) Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. Oncogene 24:980–991

    Article  PubMed  CAS  Google Scholar 

  97. Tracy K, Dibling BC, Spike BT, Knabb JR, Schumacker P, Macleod KF (2007) BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol Cell Biol 27:6229–6242

    Article  PubMed  CAS  Google Scholar 

  98. Petrank YF, Dong SJ, Tyberg J, Sideman S, Beyar R (1999) Regional differences in shape and load in normal and diseased hearts studied by three dimensional tagged magnetic resonance imaging. Int J Card Imaging 15:309–321

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Center for Pharmacogenomics, Washington University, 660 S. Euclid Ave., Campus Box 8086, St. Louis, MO, 63110, USA

    Gerald W. Dorn II

  2. Molecular Cardiovascular Research, University of Cincinnati, Cincinnati, OH, USA

    Gerald W. Dorn II & Abhinav Diwan

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  1. Gerald W. Dorn II
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  2. Abhinav Diwan
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Correspondence to Gerald W. Dorn II.

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Dorn II, G.W., Diwan, A. The rationale for cardiomyocyte resuscitation in myocardial salvage. J Mol Med 86, 1085–1095 (2008). https://doi.org/10.1007/s00109-008-0362-y

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  • DOI: https://doi.org/10.1007/s00109-008-0362-y

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