XIAP expression attenuated myocardial injury in aging hearts after myocardial ischemia and reperfusion in mice model



X-linked inhibitor of apoptosis protein (XIAP), also known as inhibitor of apoptosis protein 3 (IAP3) and baculoviral IAP repeat-containing protein 4 (BIRC), is a protein that stops apoptotic cell death. XIAP stops apoptotic cell death that is induced either by viral infection or by over-production of Caspases. The BIR2 domain of XIAP inhibits Caspase 3 and 7, while BIR3 binds to and inhibits Caspase 9. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, apoptosis occur in cardiac myocytes, and both gradual and acute cell death are hallmarks of cardiac pathology. Pharmacological and genetic inhibition of apoptosis diminishes infarct size and improves cardiac function in these disorders. Using a mouse model of ischemia/reperfusion injury to determine whether XIAP expression is improved cardiac function in aging heart after myocardial ischemia and reperfusion. The LV function indices markedly declined after myocardial I/R in aging mice (18–24 month) compared with adult mice (4-6month) as evidenced by decreased LV function and increased both Left Ventricular Diastolic Pressure and Left Ventricular End-Diastolic Pressure in aging mice. Furthermore, myocardial apoptosis was significantly higher in the aged heart when compare to the young hearts after I/R. As apoptosis of cardiomyocytes is one of the major contributors to the pathogenesis in subjects with ischemia/reperfusion injury, prevention of apoptosis may prove to be a reasonable therapeutic strategy through enhaced the activity of XIAP.

Keywords: XIAP; Aging; Ischemia/Reperfusion; LV function; Apoptosis; Myocardial injury

Copyright © 2014 by The American Society for BioMedicine and BM-Publisher, Inc.

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  1. Holcik M, Korneluk RG. Functional Characterization of the X-Linked Inhibitor of Apoptosis (XIAP) Internal Ribosome Entry Site Element: Role of La Autoantigen in XIAP Translation. Mol. Cell. Biol 2000; 20(13): 4648–57. [Article]
  2. Mozid AM, Arnous S, Sammut EC, Mathur A. Stem cell therapy for heart diseases. Br Med Bull 2011; 98:143–159. [PubMed]
  3. Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 1996; 85(6):803–815. [PubMed]
  4. Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 1997; 388(6639): 300–304. [PubMed]
  5. Duckett CS, Nava VE, Gedrich RW, Clem RJ, Van Dongen JL, Gilfillan MC, Shiels H, Hardwick JM, Thompson CB. A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors. EMBO J 1996;15(11): 2685–2694. [PMC free article] [PubMed]
  6. Hoodless PA, Haerry T, Abdollah S, Stapleton M, O'Connor MB, Attisano L, Wrana JL. MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell 1996; 85(4):489–500. [PubMed]
  7. Duckett CS, Li F, Wang Y, Tomaselli KJ, Thompson CB, Armstrong RC. Human IAP-Like Protein Regulates Programmed Cell Death Downstream of Bcl-xL and Cytochrome c. Mol. Cell. Biol 1998; 18(1): 608–15. [PubMed]
  8. Wilkinson JC, Cepero E, Boise LH, Duckett CS. Upstream Regulatory Role for XIAP in Receptor-Mediated Apoptosis. Mol. Cell. Biol 2004; 24(16): 7003–14.
  9. Oeda E, Oka Y, Miyazono K, Kawabata M. Interaction of Drosophila inhibitors of apoptosis with thick veins, a type I serine/threonine kinase receptor for decapentaplegic. J Biol Chem 1998; 273(16): 9353–9356. [PubMed]
  10. Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM, Day CL, Tikoo A, Burke R, Wrobel C, Moritz RL, Simpson RJ, Vaux DL. HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J. Biol. Chem 2000; 277(1): 445–54.
  11. Menasche P, Alfieri O, Janssens S, McKenna W, Reichenspurner H, Trinquart L et al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 2008;117:1189–1200. [Article] [PubMed]
  12. Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G, Farahani R, McLean M, Ikeda JE, MacKenzie A, Korneluk RG. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 1996; 379 (6563): 349–53.
  13. Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 1995; 83(7):1243–1252. [PubMed]
  14. Silke J, Hawkins CJ, Ekert PG, Chew J, Day CL, Pakusch M, Verhagen AM, Vaux DL. The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3– and caspase 9–interacting sites. J. Cell Biol 2002;157 (1): 115–24.
  15. Laflamme MA, Murry CE. Heart regeneration. Nature 2011; 473: 326–335. [Article] [PubMed]
  16. Duckett CS, Nava VE, Gedrich RW, Clem RJ, Van Dongen JL, Gilfillan MC, Shiels H, Hardwick JM, Thompson CB. A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors. EMBO J 1996;15(11): 2685–94.
  17. Sliwa K, Woodiwiss A, Candy G, Badenhorst D, Libhaber C, Norton G et al. Effects of pentoxifylline on cytokine profiles and left ventricular performance in patients with decompensated congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol 2002; 90:1118–1122.
  18. Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 1998;17(8): 2215–23.
  19. Vanlangenakker N, Vanden Berghe T, Krysko DV, Festjens N, Vandenabeele P. Molecular mechanisms and pathophysiology of necrotic cell death. Curr Mol Med 2008; 8: 207–220. [Article] [PubMed]
  20. Henriquez M, Armisen R, Stutzin A, Quest AF. Cell death by necrosis, a regulated way to go. Curr Mol Med 2008; 8:187–206. [Article] [PubMed]
  21. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, et al. Towards a proteome-scale map of the human protein-protein interaction network. Nature 2005; 437(7062):1173–8.
  22. Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev 2007; 87: 99–163. [Article] [PubMed]
  23. Guerra S, Leri A, Wang X, Finato N, Di Loreto C, Beltrami CA et al. Myocyte death in the failing human heart is gender dependent. Circ Res 1999; 85:856–866. [PubMed]
  24. Zhou Q, Krebs JF, Snipas SJ, Price A, Alnemri ES, Tomaselli KJ, Salvesen GS. Interaction of the baculovirus anti-apoptotic protein p35 with caspases: specificity, kinetics, and characterization of the caspase/p35 complex. Biochemistry 1998;37:10757–10765. [PubMed]
  25. French CJ, Taatjes DJ, Sobel BE. Autophagy in myocardium of murine hearts subjected to ischemia followed by reperfusion. Histochem Cell Biol 2010; 134: 519–526.
  26. Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA et al. Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ 2007;14:146–157. [ Article][PubMed]
  27. Davoodi J, Lin L, Kelly J, Liston P, MacKenzie AE . Neuronal apoptosis-inhibitory protein does not interact with Smac and requires ATP to bind caspase-9. J. Biol. Chem. 2004; 279 (39): 40622–8.
  28. Russell RR, 3rd, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M et al. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 2004;114: 495–503. [Article] [PubMed]
  29. Yan N, Wu JW, Chai J, Li W, Shi Y. Molecular mechanisms of DrICE inhibition by DIAP1 and removal of inhibition by Reaper, Hid and Grim. Nat Struct Mol Biol 2004;11: 420–428. [PubMed]
  30. Hamacher-Brady A, Brady NR, Gottlieb RA. Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem 2006; 281: 29776–29787. [Article] [PubMed]
  31. Gustafsson AB, Gottlieb RA. Autophagy in ischemic heart disease. Circ Res 2009;104:150–158. [Article] [PubMed]
  32. Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit VM. ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol 2000;10: 1359–1366. [PubMed]
  33. Buss SJ, Muenz S, Riffel JH, Malekar P, Hagenmueller M, Weiss CS et al. Beneficial effects of mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction. J Am Coll Cardiol 2009; 54: 2435–2446.
  34. Drazner MH, Rame JE, Marino EK, Gottdiener JS, Kitzman DW, Gardin JM et al. Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years: the Cardiovascular Health Study. J Am Coll Cardiol 2004; 43: 2207–2215. [PubMed]
  35. Kostin S, Pool L, Elsasser A, Hein S, Drexler HC, Arnon E et al. Myocytes die by multiple mechanisms in failing human hearts. Circ Res 2003; 92: 715–724. [Article] [PubMed]
  36. Cao DJ, Wang ZV, Battiprolu PK, Jiang N, Morales CR, Kong Y et al. Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy. Proc Natl Acad Sci USA 2011;108:4123–4128. [PubMed]
  37. EW Austin, NG Yousif, L Ao, DA, Fullerton, X Meng. Ghrelin reduces myocardial injury following global ischemia and reperfusion via suppression of myocardial inflammatory response. AJBM 2013;1(2):33-47. [Article-AJBM]
  38. Shende P, Plaisance I, Morandi C, Pellieux C, Berthonneche C, Zorzato F et al. Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice. Circulation 2011;123:1073–1082.
  39. Zhu H, Tannous P, Johnstone JL, Kong Y, Shelton JM, Richardson JA et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 2007;117:1782–1793. [Article] [PubMed]
  40. Keller T, Zeller T, Peetz D,  et al.  Sensitive troponin I assay in early diagnosis of acute myocardial infarction.  N Engl J Med 2009;361(9):868-877. [PubMed]
  41. Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS. Structural basis for the inhibition of caspase-3 by XIAP. Cell 2001;104:791–800. [PubMed]

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Research Article
DOI: http://dx.doi.org/10.18081/ajbm/2333-5106/014-04/400-421
American Journal of BioMedicine 2015, Volume 3, Issue 1, pages 18-38
Received June 22, 2014; Accepted January 15, 2015, Published February 11, 2015

How to cite this article
Matsuda SM, Nakamura J, Eikan S, et al. XIAP expression attenuated myocardial injury in aging hearts after myocardial ischemia and reperfusion in mice model. American Journal of BioMedicine 2015;3(1):18-38

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