From the First Department of Internal Medicine, Fukushima Medical
College, Hikarigaoka 1, Fukushima 960–12, Japan.
Correspondence to Yukio Maruyama, MD, Professor and Chairman, First Department of Internal Medicine, Fukushima Medical College, Hikarigaoka 1, Fukushima, 960–12, Japan. E-mail yaoita{at}cc.fmu.ac.jp
Background—Z-Val-Ala-Asp(OMe)-CH2F
(ZVAD-fmk), a tripeptide inhibitor of the caspase
interleukin-1ß–converting enzyme family of cysteine proteases, may
reduce myocardial reperfusion injury in vivo by attenuating
cardiomyocyte apoptosis within the ischemic
area at risk.
Methods and Results—Sprague-Dawley rats were subjected to a
30-minute coronary occlusion followed by a 24-hour reperfusion.
An inert vehicle (dimethylsulfoxide; group 1, n=8) or ZVAD-fmk, at a
total dose of 3.3 mg/kg (group 2, n=8), was administered
intravenously every 6 hours starting at 30 minutes before
coronary occlusion until 24 hours of reperfusion. At this
24-hour point, hemodynamics were assessed by means of
cardiac catheterization; then, the rats were killed,
and the left ventricle was excised and sliced. The myocardial infarct
size/ischemic area at risk and the count of presumed
apoptotic cardiomyocytes (terminal
deoxynucleotidyl transferase–mediated dUTP-biotin
nick end labeling [TUNEL]-positive cells) within the ischemic
area at risk were assessed through
triphenyltetrazolium chloride staining and
TUNEL methods, respectively. Peak positive left ventricular
dP/dt was higher (P=.02) and left
ventricular end-diastolic pressure was lower
(P=.04) in group 2 than in group 1. The infarct
size/ischemic area at risk of group 2 (52.4±4.0%) was smaller
(P=.02) than that of group 1 (66.6±3.7%), and
TUNEL-positive cells were fewer (P=.0002) (group 2,
3.1±0.9%; group 1, 11.1±1.0%). Agarose gel electrophoresis revealed
DNA laddering in the border zone myocardium of group 1, but
DNA ladder formation was attenuated in group 2.
Conclusions—ZVAD-fmk was effective in reducing myocardial
reperfusion injury, which could at least be partially attributed to the
attenuation of cardiomyocyte apoptosis.
© 1998 American Heart Association, Inc.
Basic Science Reports
Attenuation of Ischemia/Reperfusion Injury in Rats by a Caspase Inhibitor
Key Words: myocardium • reperfusion • apoptosis • caspase
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P A J Krijnen, R Nijmeijer, C J L M Meijer, C A Visser, C E Hack, and H W M Niessen Apoptosis in myocardial ischaemia and infarction J. Clin. Pathol., November 1, 2002; 55(11): 801 - 811. [Abstract] [Full Text] [PDF]
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 A. Iwata, J. M. Harlan, N. B. Vedder, and R. K. Winn The caspase inhibitor z-VAD is more effective than CD18 adhesion blockade in reducing muscle ischemia-reperfusion injury: implication for clinical trials Blood, August 28, 2002; 100(6): 2077 - 2080. [Abstract] [Full Text] [PDF]
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W. Chao, Y. Shen, L. Li, and A. Rosenzweig Importance of FADD Signaling in Serum Deprivation- and Hypoxia-induced Cardiomyocyte Apoptosis J. Biol. Chem., August 23, 2002; 277(35): 31639 - 31645. [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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M. Chen, D.-J. Won, S. Krajewski, and R. A. Gottlieb Calpain and Mitochondria in Ischemia/Reperfusion Injury J. Biol. Chem., August 2, 2002; 277(32): 29181 - 29186. [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. 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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 L. K. Chang and E. M. Johnson Jr. Cyclosporin A inhibits caspase-independent death of NGF-deprived sympathetic neurons: a potential role for mitochondrial permeability transition J. Cell Biol., May 28, 2002; 157(5): 771 - 781. [Abstract] [Full Text] [PDF]
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M. Shimizu, K. Fukuo, S. Nagata, T. Suhara, M. Okuro, K. Fujii, Y. Higashino, M. Mogi, Y. Hatanaka, and T. Ogihara Increased plasma levels of the soluble form of fas ligand in patients with acute myocardial infarction and unstable angina pectoris J. Am. Coll. Cardiol., February 20, 2002; 39(4): 585 - 590. [Abstract] [Full Text] [PDF]
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C. GILL, R. MESTRIL, and A. SAMALI Losing heart: the role of apoptosis in heart disease--a novel therapeutic target? FASEB J, February 1, 2002; 16(2): 135 - 146. [Abstract] [Full Text] [PDF]
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G. Horstick, O. Berg, A. Heimann, O. Gotze, M. Loos, G. Hafner, B. Bierbach, S. Petersen, S. Bhakdi, H. Darius, et al. Application of C1-Esterase Inhibitor During Reperfusion of Ischemic Myocardium: Dose-Related Beneficial Versus Detrimental Effects Circulation, December 18, 2001; 104(25): 3125 - 3131. [Abstract] [Full Text] [PDF]
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H. Ruetten, C. Badorff, C. Ihling, A. M. Zeiher, and S. Dimmeler Inhibition of caspase-3 improves contractile recovery of stunned myocardium, independent of apoptosis-inhibitory effects J. Am. Coll. Cardiol., December 1, 2001; 38(7): 2063 - 2070. [Abstract] [Full Text] [PDF]
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 C. R Holleyman and D. F Larson Apoptosis in the ischemic reperfused myocardium Perfusion, December 1, 2001; 16(6): 491 - 502. [Abstract] [PDF]
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J. Grunenfelder, D. N. Miniati, S. Murata, V. Falk, E. G. Hoyt, M. Kown, M. L. Koransky, and R. C. Robbins Upregulation of Bcl-2 Through Caspase-3 Inhibition Ameliorates Ischemia/Reperfusion Injury in Rat Cardiac Allografts Circulation, September 18, 2001; 104 (2009): I-202 - I-206. [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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G. Condorelli, R. Roncarati, J. Ross Jr., A. Pisani, G. Stassi, M. Todaro, S. Trocha, A. Drusco, Y. Gu, M. A. Russo, et al. Heart-targeted overexpression of caspase3 in mice increases infarct size and depresses cardiac function PNAS, August 1, 2001; (2001) 161120198. [Abstract] [Full Text] [PDF]
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T. Matsui, J. Tao, F. del Monte, K.-H. Lee, L. Li, M. Picard, T. L. Force, T. F. Franke, R. J. Hajjar, and A. Rosenzweig Akt Activation Preserves Cardiac Function and Prevents Injury After Transient Cardiac Ischemia In Vivo Circulation, July 17, 2001; 104(3): 330 - 335. [Abstract] [Full Text] [PDF]
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 Z. Zhou, X. Sun, and Y. J. Kang Ethanol-Induced Apoptosis in Mouse Liver : Fas- and Cytochrome c-Mediated Caspase-3 Activation Pathway Am. J. Pathol., July 1, 2001; 159(1): 329 - 338. [Abstract] [Full Text] [PDF]
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F. W. Bowen, T. Hattori, N. Narula, I. S. Salgo, T. Plappert, M. G. St. John Sutton, and L. H. Edmunds Jr Reappearance of myocytes in ovine infarcts produced by six hours of complete ischemia followed by reperfusion Ann. Thorac. Surg., June 1, 2001; 71(6): 1845 - 1855. [Abstract] [Full Text] [PDF]
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H. Fauvel, P. Marchetti, C. Chopin, P. Formstecher, and R. Neviere Differential effects of caspase inhibitors on endotoxin-induced myocardial dysfunction and heart apoptosis Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1608 - H1614. [Abstract] [Full Text] [PDF]
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T. Yamamura, H. Otani, Y. Nakao, R. Hattori, M. Osako, and H. Imamura IGF-I differentially regulates Bcl-xL and Bax and confers myocardial protection in the rat heart Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1191 - H1200. [Abstract] [Full Text] [PDF]
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 G. D. Dispersyn and M. Borgers Apoptosis in the Heart: About Programmed Cell Death and Survival Physiology, February 1, 2001; 16(1): 41 - 47. [Abstract] [Full Text] [PDF]
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 K. Kuwano, R. Kunitake, T. Maeyama, N. Hagimoto, M. Kawasaki, T. Matsuba, M. Yoshimi, I. Inoshima, K. Yoshida, and N. Hara Attenuation of bleomycin-induced pneumopathy in mice by a caspase inhibitor Am J Physiol Lung Cell Mol Physiol, February 1, 2001; 280(2): L316 - L325. [Abstract] [Full Text] [PDF]
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S. Negoro, H. Oh, E. Tone, K. Kunisada, Y. Fujio, K. Walsh, T. Kishimoto, and K. Yamauchi-Takihara Glycoprotein 130 Regulates Cardiac Myocyte Survival in Doxorubicin-Induced Apoptosis Through Phosphatidylinositol 3-Kinase/Akt Phosphorylation and Bcl-xL/Caspase-3 Interaction Circulation, January 30, 2001; 103(4): 555 - 561. [Abstract] [Full Text] [PDF]
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R. NEVIÈRE, H. FAUVEL, C. CHOPIN, P. FORMSTECHER, and P. MARCHETTI Caspase Inhibition Prevents Cardiac Dysfunction and Heart Apoptosis in a Rat Model of Sepsis Am. J. Respir. Crit. Care Med., January 1, 2001; 163(1): 218 - 225. [Abstract] [Full Text]
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 J R Thiagarajah, P Gourmelon, N M Griffiths, F Lebrun, R J Naftalin, and K C Pedley Radiation induced cytochrome c release causes loss of rat colonic fluid absorption by damage to crypts and pericryptal myofibroblasts Gut, November 1, 2000; 47(5): 675 - 684. [Abstract] [Full Text] [PDF]
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T. E. McDonald, M. N. Grinman, C. M. Carthy, and K. R. Walley Endotoxin infusion in rats induces apoptotic and survival pathways in hearts Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2053 - H2061. [Abstract] [Full Text] [PDF]
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 K. Shiraishi, K. Naito, and K.-i. Yoshida Inhibition of Calpain but Not Caspase Protects the Testis Against Injury after Experimental Testicular Torsion of Rat Biol Reprod, November 1, 2000; 63(5): 1538 - 1548. [Abstract] [Full Text]
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