Cardiac Reperfusion Injury: Aging, Lipid Peroxidation, and Mitochondrial Function

  • Luke I. Szweda
  • David T. Lucas
  • Kenneth M. Humphries
  • Pamela A. Szweda


Mitochondrial Respiration Glutamate Dehydrogenase Lipoic Acid Free Radical Production Free Radical Generation 
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  1. Ambrosio, G., Zweier, J. L., Duilio, C., Kuppusamy, P., Santoro, G., Elia, P. P., Tritto, I., Cirillo, P., Condorelli, M., Chiariello, M., and Flaherty, J. T., 1993, Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow, J. Biol. Chem. 268:18532–18541.PubMedGoogle Scholar
  2. Bagchi, D., Wetscher, G. J., Bagchi, M., Hinder, P. R., Perdikis, G., Stohs, S. J., Hinder, R. A. and Das, D.K., 1997, Interrelationship between cellular calcium homeostasis andfree radical generationin myocardial reperfusion injury, Chem. Biol. Interact. 104:65–85.PubMedGoogle Scholar
  3. Baker, J. E., and Kalyanaraman, B., 1989, Ischemia-induced changes in myocardial paramagnetic metabolites: Implications for intracellular oxy-radical generation, FEBS Lett. 244:311–314.PubMedGoogle Scholar
  4. Balaban, R. S., 1990. Regulation of oxidative phosphorylation in the mammalian cell. Am. J Physiol. 258:C377–389.Google Scholar
  5. Barlow, C. H., and Chance, B., 1976, Ischemic areas in perfused rat hearts: Measurement by NADH fluorescence photography, Science 193:909–910.PubMedGoogle Scholar
  6. Barlow, C. H., Harken, A. H., and Chance, B., 1977, Evaluation of cardiac ischemia by NADH fluorescence photography, Ann. Surg. 186:737–740.PubMedGoogle Scholar
  7. Beckman, K. B., and Ames, B. N., 1997, Oxidative decay of DNA, J. Biol. Chem. 272:19633–19636.CrossRefPubMedGoogle Scholar
  8. Beckman, K. B., and Ames, B. N. 1998, The free radical theory of aging matures, Physiol. Rev. 78: 547–581.PubMedGoogle Scholar
  9. Berlett, B. S., and Stadtman, E. R., 1997, Protein oxidation in aging disease, and oxidative stress, J. Biol. Chem. 272:20313–20316.CrossRefPubMedGoogle Scholar
  10. Bindoli, A., 1988, Lipid peroxidation in mitochondria, Free Radical Biol. Med. 5:247–261.CrossRefGoogle Scholar
  11. Blanc, H. M., Kelly, J. F., Mark, R. J., Waeg, G., and Mattson, M. P., 1997, 4-Hydroxynonenal, an aldehydic product of lipid peroxidation, impairs signal transduction associated with muscarinic acetylcholine and metabotropic glutamate receptors: Possible action on G alpha (q/11), J. Neurochem. 69:570–580.PubMedGoogle Scholar
  12. Blasig, I. E., Grune, T., Schonheit, K., Rohde, E., Jakstadt, M., Haseloff, R. F., and Siems, W. G., 1995, 4-Hydroxynonenal, a novel indicator of lipid peroxidation for reperfusion injury of the myocardium, Am. J. Physiol. 269:H14–22.Google Scholar
  13. Bolli, R., Patel, B. S., Jeroudi, M. O., Lai, E. K., and McCay, P. B., 1988, Demonstration of free radical generation in’ stunned’ myocardium ofintact dogs with the use of the spin trap alpha-phenyl N-tert-butyl nitrone [published erratum appears in J. Clin. Invest. 72(5) following 1807], J. Clin. Invest. 72:476–485.Google Scholar
  14. Boveris, A., 1984, Determination of the production of superoxide radicals and hydrogen peroxide in mitochondria, MethodsEnzymol. 105:429–435.Google Scholar
  15. Boveris, A., and Cadenas, E., 1975, Mitochondrial production of superoxide anions and its relationship to the antimycin insensitive respiration, FEBS Lett. 54:311–314.CrossRefPubMedGoogle Scholar
  16. Brown, G. C., 1992, Control of respiration and ATP synthesis in mammalian mitochondria and cells, Biochem. J. 284:1–13.PubMedGoogle Scholar
  17. Brown, J. P., and Perham, R. N., 1976, Selective inactivation of the transacylase components of the 2-oxo acid dehydrogenase multienzyme complexes of Escherichia coli, Biochem. J. 155:419–427.PubMedGoogle Scholar
  18. Cadenas, E., Boveris, A., Ragan, C. I., and Stoppani, A. O., 1977, Production of superoxide radicals and hydrogen peroxide by NADH ubiquinone reductase and ubiquinol-cytochrome c reductase from beef-heart mitochondria, Arch. Biochem Biophys. 180:248–257.CrossRefPubMedGoogle Scholar
  19. Chen, J. J., Bertrand, H., and Yu, B. P., 1995, Inhibition of adenine nucleotide translocator by lipid peroxidation products, Free Radical Biol. Med. 19:583–590.Google Scholar
  20. Cohn, J. A., Tsai, L., Friguet, B., and Szweda, L. I., 1996, Chemical characterization of a protein-4-hydroxy-2-nonenal cross-link: Immunochemical detection in mitochondria exposed to oxidative stress, Arch. Biochem. Biophys. 328:158–164.CrossRefPubMedGoogle Scholar
  21. Cooney, G. J., Taegtmeyer, H., and Newsholme, E. A., 1981, Tricarboxylic acid cycle flux and enzyme activities in the isolated working rat heart, Biochem. J. 200:701–703.PubMedGoogle Scholar
  22. Cordis, G. A., Maulik, N., Bagchi, D., Engelman, R. M., and Das, D. K., 1993, Estimation of the extent of lipid peroxidation in the ischemic and reperfused heart by monitoring lipid metabolic products with the aid of high-performance liquid chromatography, J. Chromatogr. 632:97–103.CrossRefPubMedGoogle Scholar
  23. Das, D. K., George, A., Liu, X. K., and Rao, P. S., 1989, Detection of hydroxyl radicals in the mitochondria of ischemic-reperfused myocardium by trapping with salicylate, Biochem. Biophys. Res. Commun. 165:1004–1009.PubMedGoogle Scholar
  24. Duan, J., and Karmazyn, M., 1989, Relationship between oxidative phosphorylation and adenine nucleotide translocase activity of two populations of cardiac mitochondria and mechanical recovery of ischemic hearts following reperfusion, Can. J. Physiol. Pharmacol. 67:704–709.PubMedGoogle Scholar
  25. Estabrook, R. W., 1962, Fluorometric measurement of reduced pyridine nucleotide in cellular and subcellular particles, Anal. Biochem. 4:231–245.CrossRefPubMedGoogle Scholar
  26. Esterbauer, H., Schaur, R.J., and Zollner, H., 1991, Chemistryandbiochemistryof 4-hydroxynonenal, malonaldehyde, and related aldehydes, Free Radical Biol. Med. 11:81–128.CrossRefGoogle Scholar
  27. Faulk, E. A., McCully, J. D., Hadlow, N. C., Tsukube, T., Krukenkamp, I. B., Federman, M., and Levitsky, S., 1995a, Magnesium cardioplegia enhances mRNA levels and maximal velocities of cytochrome oxidase I in the senescent myocardium during global ischemia, Circulation 92:11405–11412.Google Scholar
  28. Faulk, E. A., McCully, J. D., Tsukube, T., Hadlow, N. C., Krukenkamp, I. B., and Levitsky, S., 1995b, Myocardial mitochondrial calcium accumulation modulates nuclear calcium accumulation and DNA fragmentation, Ann. Thorac. Surg. 60:338–344.PubMedGoogle Scholar
  29. Ferrari, R., 1996, The role of mitochondria in ischemic heart disease, J. Cardiovasc. Pharmacol. 28:S1–10.Google Scholar
  30. Friguet, B., Stadtman, E. R., and Szweda, L. I., 1994, Modification of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal: Formation of cross-linked protein that inhibits the multicatalytic protease, J. Biol. Chem. 269:21639–21643.PubMedGoogle Scholar
  31. Giulivi, C., Boveris, A., and Cadenas, E., 1995, Hydroxyl radical generation during mitochondrial electron transfer and the formation of 8-hydroxydesoxyguanosine in mitochondria] DNA, Arch. Biochem. Biophys. 316:909–916.CrossRefPubMedGoogle Scholar
  32. Grill, H. P., Flaherty, J. T., Zweier, J.L., Kuppusamy, P., and Weisfeldt, M. L., 1992, Direct measurement of myocardial free radical generation in an in vivo model: Effects of postischemic reperfusion and treatment with human recombinant superoxide dismutase, J. Am. Coll. Cardiol. 21:1604–1611.Google Scholar
  33. Hansford, R. G., 1983, Bioenergetics in aging, Biochem. Biophys. Acta 726:41–80.PubMedGoogle Scholar
  34. Henle, E. S., and Linn, S., 1997, Formation, prevention, and repair of DNA damage by iron/hydrogen peroxide, J. Biol. Chem. 272:19095–19098.CrossRefPubMedGoogle Scholar
  35. Humphries, K. M., and Szweda, L. I., 1998, Selective inactivation of α-ketoglutaratede hydrogenase: Reaction of lipoic acid with 4-hydroxy-2-nonenal, Biochemistry 37:15835–15841.PubMedGoogle Scholar
  36. Humphries, K. M., Yoo, Y., and Szweda, L. I., 1998, Inhibition of NADH-linked mitochondrial respiration by 4-hydroxy-2-nonenal, Biochemistry 37:552–557.PubMedGoogle Scholar
  37. Keller, J. N., Mark, R. J., Brace, A. J., Blanc, E., Rothstein, J. D., Uchida, K., Waeg, G., and Mattson, M. P., 1997, 4-Hydroxynonenal, an aldehydic product of membrane lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes, Neuroscience 80:685–696.CrossRefPubMedGoogle Scholar
  38. Kramer, J.H., Misik, V., and Weglicki, W.B., 1994, Lipid peroxidation-derivedfreeradicalproduction and postischemic myocardial reperfusion injury, Ann NY Acad Sci 723:180–196.PubMedGoogle Scholar
  39. Kuzuya, T., Hoshida, S., Kim, Y., Nishida, M., Fuji, H., Kitabatake, A., Tada, M., and Kamada, T., 1990, Detection of oxygen-derived free radical generation in the canine postischemic heart during late phase of repertusion, Circ. Res. 66:1160–1165.PubMedGoogle Scholar
  40. Lucas, D. T., and Szweda, L. I., 1998, Cardiac reperfusion injury: Aging, lipid peroxidation, and mitochondrial dysfunction, Proc. Natl. Acad. Sci. USA 95:510–514.CrossRefPubMedGoogle Scholar
  41. Lucas, D. T., and Szweda, L. I., 1999, Declines in mitochondrial respiration during cardiac reperfusion: Age-dependent inactivation of alpha-ketoglutarate dehydrogenase, Proc. Natl Acad. Sci. USA 96:6689–6693.CrossRefPubMedGoogle Scholar
  42. Maas, E., and Bisswanger, H., 1990, Localization of the alpha-oxoacid dehydrogenase multienzyme complexes within the mitochondrion, FEBS Lett. 277:189–190.CrossRefPubMedGoogle Scholar
  43. Mark, R. J., Lovell, M. A., Markesbery, W. R., Uchida, K., and Mattson, M. P., 1997, A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide, J. Neurochem. 68:255–264.PubMedGoogle Scholar
  44. Matsuda, H., McCully, J. D., and Levitsky, S., 1997, Developmental differences in cytosolic calcium accumulation associated with global ischemia: Evidence for differential intracellular calcium channel receptor activity, Circulation. 96:II233–238; discussion II238-239.Google Scholar
  45. McCord, J. M., 1988, Free radicals and myocardial ischemia: Overview and outlook, Free Radical Biol. Med.. 4:9–14.CrossRefGoogle Scholar
  46. Moreno-Sanchez, R., Hogue, B. A., and Hansford, R. G., 1990, Influence of NAD-linked dehydrogenase activity on flux through oxidative phosphorylation, Biochem. J. 268:421–428.PubMedGoogle Scholar
  47. Nohl, H., and Hegner, D., 1978, Do mitochondria produce oxygen radicals in vivo?, Eur. J. Biochem. 82:563–567.CrossRefPubMedGoogle Scholar
  48. Nohl, H., Breuninger, V, and Hegner, D., 1978, Influence of mitochondrial radical formation on energy-linked respiration, Eur. J. Biochem. 90:385–390.CrossRefPubMedGoogle Scholar
  49. Otani, H., Tanaka, H., Inoué, T., Umemoto, M., Omoto, K., Tanaka, K., Sato, T., Osako, T., Masuda, A., Nonoyama, A., and Kagawa, T., 1984, In vitro study on contribution of oxidative metabolism of isolated rabbit heart mitochondria to myocardial reperfusion injury, Circ. Res. 55:168–175.PubMedGoogle Scholar
  50. Perham, R. N.,1991, Domains, motifs, and linkers in 2-oxo acid dehydrogenase multienzyme complexes: A paradigm in the design of a multifunctional protein, Biochemistry 30:8501–8512.Google Scholar
  51. Porpaczy, Z., Sumegi, B., and Alkonyi, I., 1987, Interaction between NAD-dependent isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase complex, and NADH: ubiquinone oxidoreductase, J. Biol. Chem. 262:9509–9514.PubMedGoogle Scholar
  52. Reed, L. J., 1974, Multienzyme complexes, Ace. Chem. Res. 7:40–46.Google Scholar
  53. Reimer, K. A., and Jennings, R. B., 1992, Myocardial ischemia, hypoxia, and infarction, in The Heart and Cardiovascular System (H. A. Fozzard, E. Haber, R. B. Jennings, A. M. Katz, and H. E. Morgan Eds.) Raven Press, New York, pp. 1875–1973.Google Scholar
  54. Rokutan, K., Kawai, K., and Asada, K., 1987, Inactivation of 2-oxoglutarate dehydrogenase in rat liver mitochondria by its substrate and t-butyl hydroperoxide, J. Biochem. (Tokyo) 101:415–422.PubMedGoogle Scholar
  55. Sayre, L. M., Zelasko, D. A., Harris, P. L., Perry, G., Salomon, R. G., and Smith, M. A., 1997, 4-Hydroxynonenalderived advanced lipid peroxidation end products are increased in Alzheimer’sdisease, J. Neurochem. 68:2092–2097.PubMedGoogle Scholar
  56. Shigenaga, M. K., Hagen, T. M., and Ames, B. N., 1994, Oxidative damage and mitochondrial decay in aging, Proc. Natl. Acad. Sci. USA 91:10771–10778.PubMedGoogle Scholar
  57. Stadtman, E. R., 1992, Protein oxidation and aging, Science 257:1220–1224.PubMedGoogle Scholar
  58. Szweda, L. I., and Stadtman, E. R., 1992, Iron-catalyzed oxidative modification of glucose-6-phosphate dehydrogenase from Leuconostoc mesenteroides: Structural and functional changes, J. Biol. Chem. 267:3096–3100.PubMedGoogle Scholar
  59. Szweda, L. I., Uchida, K., Tsai, L., and Stadtman, E. R., 1993, Inactivation of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal. Selective modification of an active-site lysine, J. Biol. Chem. 268:3342–3347.PubMedGoogle Scholar
  60. Tsai, L., and Sokoloski, E. A., 1995, The reaction of 4-hydroxy-2-nonenal with N alpha-acetyl-L-histidine, Free Radical Biol. Med. 19:39–44CrossRefGoogle Scholar
  61. Tsai, L., Szweda, P. A., Vinogradova, O., and Szweda, L. I., 1998, Structural characterization and immunochemical detection of a fluorophore derived from 4-hydroxy-2-nonenal and lysine, Proc. Natl. Acad. Sci. USA 95:7975–7980.PubMedGoogle Scholar
  62. Turrens, J. F., and Boveris, A., 1980, Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria, Biochem. J. 191:421–427.PubMedGoogle Scholar
  63. Uchida, K., and Stadtman, E. R., 1993, Covalent attachment of 4-hydroxynonenal to glyceraldehyde-3-phosphate dehydrogenase: A possible involvement of intra-and intermolecular cross-linking reaction, J. Biol. Chem. 268:6388–6393.PubMedGoogle Scholar
  64. Uchida, K., Szweda, L. I., Chae, H. Z., and Stadtman, E. R., 1993, Immunochemical detection of 4-hydroxynonenal protein adducts in oxidized hepatocytes, Proc. Natl. Acad. Sci. USA 90:8742–8746.PubMedGoogle Scholar
  65. Ueta, H., Ogura, R., Sugiyama, M., Kagiyama, A., and Shin, G., 1990, 02 partly spin trapping on cardiac submitochondrial particles isolated from ischemic and non-ischemic myocardium, J. Mol. Cell. Cardiol. 22:893–899.CrossRefPubMedGoogle Scholar
  66. Ullrich, O., Siems, W. G., Lehmann, K., Huser, H., Ehrlich, W., and Grune, T., 1996, Inhibition of poly(ADP-ribose) formation by 4-hydroxynonenal in primary cultures of rabbit synovial fibroblasts, Biochem. J., 315:705–708.PubMedGoogle Scholar
  67. Veitch, K., Hombroeckx, A., Caucheteux, D., Pouleur, H., and Hue, L., 1992, Global ischaemia induces a biphasic response of the mitochondrial respiratory chain: Anoxic pre-perfusion protects against ischaemic damage, Biochem. J. 281:709–715.PubMedGoogle Scholar
  68. Zweier, J. L., 1988, Measurement of superoxide-derived free radicals in the reperfused heart. Evidence for a free radical mechanism of reperfusion injury, J. Biol. Chem. 263:1353–1357.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Luke I. Szweda
    • 1
  • David T. Lucas
    • 1
  • Kenneth M. Humphries
    • 1
  • Pamela A. Szweda
    • 1
  1. 1.Department of Physiology and Biophysics, School of MedicineCase Western Reserve UniversityCleveland

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