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the Department of Physiology, Faculty of Medicine, University of Ottawa (Canada).
Correspondence to Henry Fliss, PhD, Department of Physiology, Faculty of Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, Ontario K1H 8M5, Canada. E-mail hfliss@labsun1.med.uottawa.ca.
Apoptosis has been observed previously in hearts subjected to either continuous ischemia or ischemia followed by reperfusion. The purpose of this study was to compare the timing and extent of apoptosis in both continuously ischemic and reperfused myocardium. We show that rats subjected to continuous coronary artery occlusion display characteristic signs of apoptosis solely in the ischemic myocardium after only 2.25 hours of ischemia, as illustrated by positive in situ end labeling (ISEL) of apoptotic cardiomyocyte nuclei in tissue sections and/or the presence of DNA "ladders" in agarose gels. In contrast, reperfusion after a 45-minute occlusion accelerated the process, with apoptosis becoming evident solely in the reperfused myocardium after only 1 hour of reperfusion. ISEL and DNA ladder intensity increased with duration of ischemia or reperfusion. The volume of myocardium in which ISEL was observed was smaller in the reperfused hearts, and the ISEL-stained nuclei represented 23% and 33% of the total nuclei in the reperfused and permanently occluded myocardium, respectively. Therefore, the data suggest that reperfusion lowers the extent of apoptosis in ischemic myocardium but, paradoxically, accelerates the residual apoptosis, possibly because of reperfusion injury. A large accumulation of neutrophils was observed in both the permanently occluded and reperfused myocardium, suggesting that the inflammatory response may have contributed to apoptosis in both settings. This study therefore confirms that both ischemic and reperfused rat myocardium can undergo apoptotic cell death. However, the data suggest that although reperfusion lowers the number of myocytes undergoing apoptosis, it accelerates apoptosis in the nonsalvageable cells.
Key Words: apoptosis myocardial ischemia reperfusion injury neutrophil
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A. Abbate, R. Bussani, G. G.L. Biondi-Zoccai, R. Rossiello, F. Silvestri, F. Baldi, L. M. Biasucci, and A. Baldi Persistent Infarct-Related Artery Occlusion Is Associated With an Increased Myocardial Apoptosis at Postmortem Examination in Humans Late After an Acute Myocardial Infarction Circulation, August 27, 2002; 106(9): 1051 - 1054. [Abstract] [Full Text] [PDF] |
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Z.-Q. Zhao and J. Vinten-Johansen Myocardial apoptosis and ischemic preconditioning Cardiovasc Res, August 15, 2002; 55(3): 438 - 455. [Abstract] [Full Text] [PDF] |
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T. Date, A. J Belanger, S. Mochizuki, J. A Sullivan, L. X Liu, A. Scaria, S. H Cheng, R. J Gregory, and C. Jiang Adenovirus-mediated expression of p35 prevents hypoxia/reoxygenation injury by reducing reactive oxygen species and caspase activity Cardiovasc Res, August 1, 2002; 55(2): 309 - 319. [Abstract] [Full Text] [PDF] |
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G.D. Dispersyn, L. Mesotten, B. Meuris, A. Maes, L. Mortelmans, W. Flameng, F. Ramaekers, and M. Borgers Dissociation of cardiomyocyte apoptosis and dedifferentiation in infarct border zones Eur. Heart J., June 1, 2002; 23(11): 849 - 857. [Abstract] [Full Text] [PDF] |
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G. Yaniv, M. Shilkrut, R. Lotan, G. Berke, S. Larisch, and O. Binah Hypoxia predisposes neonatal rat ventricular myocytes to apoptosis induced by activation of the Fas (CD95/Apo-1) receptor: Fas activation and apoptosis in hypoxic myocytes Cardiovasc Res, June 1, 2002; 54(3): 611 - 623. [Abstract] [Full Text] [PDF] |
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B. ZINGARELLI, P. W. HAKE, Z. YANG, M. O'CONNOR, A. DENENBERG, and H. R. WONG Absence of inducible nitric oxide synthase modulates early reperfusion-induced NF-{kappa}B and AP-1 activation and enhances myocardial damage FASEB J, March 1, 2002; 16(3): 327 - 342. [Abstract] [Full Text] [PDF] |
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S. Ruiz-Santana, A. Lopez, S. Torres, A. Rey, A. Losada, L. Latasa, J. L. Manzano, and B. N. Diaz-Chico Prevention of Dexamethasone-Induced Lymphocytic Apoptosis in the Intestine and in Peyer Patches by Enteral Nutrition JPEN J Parenter Enteral Nutr, November 1, 2001; 25(6): 338 - 345. [Abstract] [PDF] |
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J. Shiraishi, T. Tatsumi, N. Keira, K. Akashi, A. Mano, S. Yamanaka, S. Matoba, J. Asayama, T. Yaoi, S. Fushiki, et al. Important role of energy-dependent mitochondrial pathways in cultured rat cardiac myocyte apoptosis Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1637 - H1647. [Abstract] [Full Text] [PDF] |
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K. Suzuki, B. Murtuza, R. T. Smolenski, I. A. Sammut, N. Suzuki, Y. Kaneda, and M. H. Yacoub Overexpression of Interleukin-1 Receptor Antagonist Provides Cardioprotection Against Ischemia-Reperfusion Injury Associated With Reduction in Apoptosis Circulation, September 18, 2001; 104 (2009): I-308 - I-313. [Abstract] [Full Text] [PDF] |
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B. Stadler, J. Phillips, Y. Toyoda, M. Federman, S. Levitsky, and J. D. McCully Adenosine-enhanced ischemic preconditioning modulates necrosis and apoptosis: effects of stunning and ischemia-reperfusion Ann. Thorac. Surg., August 1, 2001; 72(2): 555 - 563. [Abstract] [Full Text] [PDF] |
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T. Scarabelli, A. Stephanou, N. Rayment, E. Pasini, L. Comini, S. Curello, R. Ferrari, R. Knight, and D. Latchman Apoptosis of Endothelial Cells Precedes Myocyte Cell Apoptosis in Ischemia/Reperfusion Injury Circulation, July 17, 2001; 104(3): 253 - 256. [Abstract] [Full Text] [PDF] |
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H. Liu, B. C. McPherson, and Z. Yao Preconditioning attenuates apoptosis and necrosis: role of protein kinase C{epsilon} and -{delta} isoforms Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H404 - H410. [Abstract] [Full Text] [PDF] |
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E. Palojoki, A. Saraste, A. Eriksson, K. Pulkki, M. Kallajoki, L.-M. Voipio-Pulkki, and I. Tikkanen Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2726 - H2731. [Abstract] [Full Text] [PDF] |
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G.-W. Wang, Z. Zhou, J. B. Klein, and Y. J. Kang Inhibition of hypoxia/reoxygenation-induced apoptosis in metallothionein-overexpressing cardiomyocytes Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2292 - H2299. [Abstract] [Full Text] [PDF] |
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Z. Chen, C. C. Chua, Y.-S. Ho, R. C. Hamdy, and B. H. L. Chua Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2313 - H2320. [Abstract] [Full Text] [PDF] |
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P. S. RAY, J. L. MARTIN, E. A. SWANSON, H. OTANI, W. H. DILLMANN, and D. K. DAS Transgene overexpression of {alpha}B crystallin confers simultaneous protection against cardiomyocyte apoptosis and necrosis during myocardial ischemia and reperfusion FASEB J, February 1, 2001; 15(2): 393 - 402. [Abstract] [Full Text] [PDF] |
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Y.-P. Wang, H. Xu, K. Mizoguchi, M. Oe, and H. Maeta Intestinal ischemia induces late preconditioning against myocardial infarction: a role for inducible nitric oxide synthase Cardiovasc Res, February 1, 2001; 49(2): 391 - 398. [Abstract] [Full Text] [PDF] |
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J.-F. Wang, X. Ren, J. DeAngelis, J. Min, Y. Zhang, T. G. Hampton, I. Amende, and J. P. Morgan Differential Patterns of Cocaine-Induced Organ Toxicity in Murine Heart versus Liver Experimental Biology and Medicine, January 1, 2001; 226(1): 52 - 60. [Abstract] [Full Text] |
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A. Bergh, O. Collin, and E. Lissbrant Effects of Acute Graded Reductions in Testicular Blood Flow on Testicular Morphology in the Adult Rat Biol Reprod, January 1, 2001; 64(1): 13 - 20. [Abstract] [Full Text] |
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Y. Xu, A. S. Clanachan, and B. I. Jugdutt Enhanced Expression of Angiotensin II Type 2 Receptor, Inositol 1,4,5-Trisphosphate Receptor, and Protein Kinase C{epsilon} During Cardioprotection Induced by Angiotensin II Type 2 Receptor Blockade Hypertension, October 1, 2000; 36(4): 506 - 510. [Abstract] [Full Text] [PDF] |
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K. Yasui, K. Kada, M. Hojo, J.-K. Lee, K. Kamiya, J. Toyama, T. Opthof, and I. Kodama Cell-to-cell interaction prevents cell death in cultured neonatal rat ventricular myocytes Cardiovasc Res, October 1, 2000; 48(1): 68 - 76. [Abstract] [Full Text] [PDF] |
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E. A. W. J. Dumont, L. Hofstra, W. L. van Heerde, S. van den Eijnde, P. A. F. Doevendans, E. DeMuinck, M. A. R. C. Daemen, J. F. M. Smits, P. Frederik, H. J. J. Wellens, et al. Cardiomyocyte Death Induced by Myocardial Ischemia and Reperfusion : Measurement With Recombinant Human Annexin-V in a Mouse Model Circulation, September 26, 2000; 102(13): 1564 - 1568. [Abstract] [Full Text] [PDF] |
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S. Mustapha, A. Kirshner, D. De Moissac, and L. A. Kirshenbaum A direct requirement of nuclear factor-kappa B for suppression of apoptosis in ventricular myocytes Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H939 - H945. [Abstract] [Full Text] [PDF] |
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P. M. Kang, A. Haunstetter, H. Aoki, A. Usheva, and S. Izumo Morphological and Molecular Characterization of Adult Cardiomyocyte Apoptosis During Hypoxia and Reoxygenation Circ. Res., July 21, 2000; 87(2): 118 - 125. [Abstract] [Full Text] [PDF] |
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Yi Xu, V. Menon, and B. I Jugdutt Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activation of protein kinase C-{varepsilon} in acutely reperfused myocardial infarction in the dog: Effect of UP269-6 and losartan on AT1- and AT2-receptor expression and IP3 receptor and PKC{varepsilon} proteins Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 184 - 195. [Abstract] [PDF] |
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S. W. Schaffer, C. B. Croft, and V. Solodushko Cardioprotective effect of chronic hyperglycemia: effect on hypoxia-induced apoptosis and necrosis Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1948 - H1954. [Abstract] [Full Text] [PDF] |
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