Oxygen Free Radicals in Heart Disease

Novel Therapies
  • Elizabeth Roth
  • Laszlo Hejjel
Part of the Methods in Pharmacology and Toxicology book series (MIPT)


During evolutionary processes, the development of aerobic metabolism has led to the liberation of reactive oxygen species (ROS) in living creatures by leakage from terminal oxidation and other enzymatic processes even under physiological conditions. Free radicals have unpaired electrons on their outer orbit, which makes these short-lived molecular fragments highly reactive with biomolecules, such as lipids, proteins, nucleic acids, and carbohydrates. These reactions are self-perpetuating chain reactions, further increasing their destructive potential. Excessive amounts of free radicals can significantly impair cellular structure and function and even can induce different forms of cell death. The development of inheritable adaptation mechanisms against oxidative stress improved the survival of the individual and the species in general as a benefit of selection (1,2). The comprehensive role of ROS in intracellular signaling mechanisms during physiological circumstances has later been recognized (3). The formation, actions and inactivation of free radicals are summarized in Fig. 1.
Fig. 1.

The generation, detoxification, and biological effects of ROS


Reactive Oxygen Species Nitric Oxide Reperfusion Injury Heart Outcome Prevention Evaluation Prevent Lipid Peroxidation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Benzie, I. F. F. (2000) Evolution of antioxidant defence mechanisms. Eur. J. Nutr. 39, 53–61.PubMedGoogle Scholar
  2. 2.
    Maxwell, S R. J. and Lip, G Y. H. (1997) Reperfusion injury: A review of the pathophysiology, clinical manifestations and therapeutic options. Int. J. Cardiol. 58, 95–117.PubMedGoogle Scholar
  3. 3.
    Bourdon, E. and Blache, D. (2001) The importance of proteins in defense against oxidation. Antiox. Redox Sign. 3, 293–311.Google Scholar
  4. 4.
    Bolli, R. (1998) Causative role of oxyradicals in myocardial stunning: A proven hypothesis. Basic. Res. Cardiol. 93, 156–162.PubMedGoogle Scholar
  5. 5.
    Das, D K., Engelman, R M., Liu, X., Maity, S., Rousou, J. A., Flack, J., et al. (1992) Oxygen-derived free radicals and hemolysis during open heart surgery. Mol. Cell. Biochem. 111, 77–86.PubMedGoogle Scholar
  6. 6.
    Singal, P K, Khaper, N., Palace, V., and Kumar, D. (1998) The role of oxidative stress in the genesis of heart disease. Cardiovasc. Res. 40, 426–432.PubMedGoogle Scholar
  7. 7.
    Hejjel, L. and Roth, E. (2000) Molecular, cellular, and clinical aspects of myocardial ischemia. Orv. Hetil. 141, 539–546.PubMedGoogle Scholar
  8. 8.
    Toufektsian, M C., Boucher F R., Morel, T S., and De Leiris, J G. (2001) Cardiac toxicity of singlet oxygen: Implication in reperfusion injury. Antiox. Redox Sign. 3, 63–69.Google Scholar
  9. 9.
    Das, D K. (2001) Redox regulation of cardiomyocyte survival and death. Antiox. Redox Sign. 3, 23–37.Google Scholar
  10. 10.
    Griendling, K K. and Ushio-Fukai, M. (2000) Reactive oxygen species as mediators of angiotensin II signaling. Regul. Pept. 91, 21–27.PubMedGoogle Scholar
  11. 11.
    Irani, K. (2000) Oxidant signaling in vascular cell growth, death, and survival. Circ. Res. 87, 179–183.PubMedGoogle Scholar
  12. 12.
    Webster, K A., Prentice, H., and Bishopric, N H. (2001) Oxidation of zinc finger transcription factors: Physiological consequences. Antiox. Redox Sign. 3, 535–548.Google Scholar
  13. 13.
    Okabe, E., Tsujimoto, Y., and Kobayashi, Y. (2000) Calmodulin and cyclic ADP-ribose interaction in Ca signaling related to cardiac sarcoplasmic reticulum: Superoxide anion radical-triggered Ca-release. Antiox. Redox Signal. 2, 47–54.Google Scholar
  14. 14.
    Goldhaber, J I. and Qayyum, M S. (2000) Oxygen free radicals and excitation-contraction coupling. Antiox. Redox Signal. 2, 55–64.Google Scholar
  15. 15.
    Agrawal, A. and Kale, R K. (2001) Radiation induced peroxidative damage: Mechanism and significance. Indian J. Exp. Biol. 39, 291–309.PubMedGoogle Scholar
  16. 16.
    Entman, M L. and Smith, C W. (1994) Postreperfusion inflammation: A model for reaction to injury in cardiovascular disease. Cardiovasc. Res. 28, 1301–1311.PubMedGoogle Scholar
  17. 17.
    Griendling, K K., Sorescu, D., and Ushio-Fukai, M. (2000) NAD(P)H oxidase. Role in cardiovascular biology and disease. Circ. Res. 86, 494–501.PubMedGoogle Scholar
  18. 18.
    Cai, H. and Harrison, D G. (2000) Endothelial dysfunction in cardiovascular diseases. The role of oxidant stress. Circ. Res. 87, 840–844.PubMedGoogle Scholar
  19. 19.
    Trochu, J.-N., Bouhour, J.-B., Kaley, G., and Hintze, T H. (2000) Role of endothelium-derived nitric oxide in the regulation of cardiac oxygen metabolism. Circ. Res. 87, 1108–1117.PubMedGoogle Scholar
  20. 20.
    Dhalla, N. S., Elmoselhi, A B., Hata, T., and Makino, N. (2000) Status of myocardial antioxidants in ischemia-reperfusion injury. Cardiovasc. Res. 47, 446–456.PubMedGoogle Scholar
  21. 21.
    Engelhardt, J. F., Sen, C K., and Oberley, L. (2001) Redox-modulating gene therapies for human diseases. Antiox. Redox Sign. 3, 341–346.Google Scholar
  22. 22.
    Guidot, D. M., Repine, J. E., Kitlowski, A. D., Flores, S. C., Nelson, S. K., Wright, R. M., et al. (1995) Mitochondrial respiration scavenges extramitochondrial superoxide via non-enzymatic mechanism. Clin. Invest. 96, 1131–1136.Google Scholar
  23. 23.
    Wang, X. L., Adachi, T., Sim, A. S., and Wilcken, D. E. (1998) Plasma extracellular superoxide dismutase levels in an Australian population with coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 18, 1915–1921.PubMedGoogle Scholar
  24. 24.
    Benjamin, I. J. and McMillan, D. R. (1998) Stress (heat shock) proteins. Molecular chaperones in cardiovascular biology and disease. Circ. Res. 83, 117–132.PubMedGoogle Scholar
  25. 25.
    Das, U. N. (2000) Free radicals, cytokines and nitric oxide in cardiac failure and myocardial infarction. Mol. Cell. Biochem. 215, 145–152.PubMedGoogle Scholar
  26. 26.
    Chen, W., Gabel, S., Steenberger, C., and Murphy, E. (1995) A redox-based mechanism for cardioprotection induced by ischemic preconditioning in perfused rat heart. Circ. Res. 77, 424–429.PubMedGoogle Scholar
  27. 27.
    Cohen, M. V., Yang, X-M., Liu, G. S., Heusch, G., and Downey, J. M. (2001) Acetylcholine, bradykinin, opioids, and phenylephrine, but not adenosine, trigger preconditioning by generating free radicals and opening mitochondrial KATP channels. Circ. Res. 89, 273–278.PubMedGoogle Scholar
  28. 28.
    Tanaka, M., Fujiwara, H., Yamasaki, K., and Sasayama, S. (1994) Superoxide dismutase and N-2-mercaptopropionyl glycine attenuate infarct size limitation effect of ischemic preconditioning in the rabbit. Cardiovasc. Res. 28, 980–986.PubMedGoogle Scholar
  29. 29.
    Yamashita, N., Hoshida, S., Taniguchi, N., Kuzuya, T., and Hori, M. (1998) Whole-body hyperthermia provides biphasic cardioprotection against ischemia/reperfusion injury in the rat. Circulation 98, 1414–1421.PubMedGoogle Scholar
  30. 30.
    Tritto, I. and Ambrosio, G. (2001) Role of oxidants in the signaling pathway of preconditioning. Antiox. Redox Sign. 3, 3–10.Google Scholar
  31. 31.
    Siwik, D. A., Pagano, P. J., and Colucci, W. S. (2001) Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am. J. Physiol. 280, C53–C60.Google Scholar
  32. 32.
    Szibor, M., Richter, C., and Ghafourifar, P. (2001) Redox control of mitochondrial functions. Antiox. Redox Sign. 3, 515–523.Google Scholar
  33. 33.
    Semenza, G. L. (2000) Cellular and molecular dissection of reperfusion injury. ROS within and without. Circ. Res. 86, 117–118.PubMedGoogle Scholar
  34. 34.
    Rakhit, R. D. and Marber, M. S. (2001) Nitric oxide: An emerging role in cardioprotection? Heart 86, 368–372.PubMedGoogle Scholar
  35. 35.
    Wink, D. A., Miranda, K. M., Espey, M. G., Pluta, R. M., Hewett, S. J., Colton, C., et al. (2001) Mechanism of the antioxidant effects of nitric oxide. Antiox. Redox Sign. 3, 203–213.Google Scholar
  36. 36.
    Cooke, J. P. (1998) Nutriceuticals for cardiovascular health. Am. J. Cardiol. 82, 43S–46S.PubMedGoogle Scholar
  37. 37.
    Guigliano, D. (2000) Dietary antioxidants for cardiovascular prevention. Nutr. Metab. Cardiovasc. Dis. 10, 38–44.Google Scholar
  38. 38.
    Pryor, W. (2000) Vitamin E and heart disease: Basic science to clinical intervention trials. Free Rad. Biol. Med. 28, 141–164.PubMedGoogle Scholar
  39. 39.
    Sethi, R., Takeda, N., Nagano, M., and Dhalla, N. S. (2000) Beneficial effects of vitamin E treatment in acute myocardial infarction. J. Cardiovasc. Pharmacol. Ther. 5, 51–58.PubMedGoogle Scholar
  40. 40.
    Kritchevsky, S. B., Shimakawa, T., Tell, G. S., et al. (1995) carotid artery wall thickness. The ARIC Study. Atherosclerosis Risk in Communities Study. Circulation 92, 2142–2150.PubMedGoogle Scholar
  41. 41.
    Hodis, H. N., Mack, W J., LaBree, L., et al. (1995) Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA 273, 1849–1854.PubMedGoogle Scholar
  42. 42.
    Stephens, N. G., Parsons, A., Schofield, P. M., Kelly, F., Cheeseman, K., and Mitchinson, M. J. (1996) Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 347, 781–786.PubMedGoogle Scholar
  43. 43.
    GISSI (1999) Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 354, 447–455.Google Scholar
  44. 44.
    Rimm, E. B., Stampfer, M. J., Ascherio, A., Giovannucci, E., Colditz, G. A., and Willett, W. C. (1993) Vitamin E consumption and the risk of coronary heart disease in men. N. Engl. J. Med. 328, 1450–1456.PubMedGoogle Scholar
  45. 45.
    Stampfer, M. J., Hennekens, C. H., Manson, J. E., Colditz, G. A., Rosner, B., and Willett, W. C. (1993) Vitamin E consumption and the risk of coronary disease in women. N. Engl. J. Med. 328, 1444–1449.PubMedGoogle Scholar
  46. 46.
    Yusuf, S., Dagenais, G., Pogue, J., Bosch, J., and Sleight, P. (2000) Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N. Engl. J. Med 342, 154–160.PubMedGoogle Scholar
  47. 47.
    Lonn, E., Yusuf, S., Dzavik, V., Doris, C., Yi, Q., Smith, S., et al., for the SECURE Investigators. (2001) Effects of ramipril and vitamin E on atherosclerosis: The study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation 103, 919–925.PubMedGoogle Scholar
  48. 48.
    Solzbach, U., Hornig, B., Jeserich, M., and Just, H. (1997) Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients. Circulation 96, 1513–1519.PubMedGoogle Scholar
  49. 49.
    Hornig, B., Arakawa, N., Kohler, C., and Drexler, H. (1998) Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation 97, 363–368.PubMedGoogle Scholar
  50. 50.
    Yokoyama, H., Lingle, D. M., Crestanello, J. A., Kamelgard, J., Kott, B. R., Momeni, R., et al. (1996) Coenzyme Q10 protects coronary endothelial function from ischemia reperfusion injury via an antioxidant effect. Surgery 120, 189–196.PubMedGoogle Scholar
  51. 51.
    Tran, M. T., Mitchell, T. M., Kennedy, D. T., and Giles, J. T. (2001) Role of coenzyme Q10 in chronic heart failure, angina, and hypertension. Pharmacotherapy 21, 797–806.PubMedGoogle Scholar
  52. 52.
    Miller, A. L. (1996) Antioxidant flavonoids: Structure, function and clinical usage. Alt. Med. Rev. 1, 103–111.Google Scholar
  53. 53.
    Hultzquist, D. E., Xu, F., Quandt, K. S., Shlafer, M., Mack, C. P., Till, G. O., et al. (1993) Evidence that NADPH-dependent methemoglobin reductase and administered riboflavin protect tissues from oxidative injury. Am. J. Hematol. 42, 13–18.Google Scholar
  54. 54.
    Herrog, M. G. L., Feskens, E. J. M., Hollman, P. C. H., Katman, M. B., and Krombout, D. (1993) Dietary antioxidant flavonoids and risk of coronary heart disease: The Zutphen elderly study. Lancet 342, 1007–1011.Google Scholar
  55. 55.
    Knekt, P., Reunanen, A., Järvinen, R., Seppänen, R., Heliövaara, M., and Aromaa, A. (1994) Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am. J. Eepidemiol. 139, 1180–1189.Google Scholar
  56. 56.
    Rimm, E. B., Katan, M. B., Ascherio, A., Stampfer, M. J., and Willett, W. C. (1996) Relation between intake of flavonoids and risk for coronary heart disease in male health professionals. Ann. Intern. Med. 125, 384–389.PubMedGoogle Scholar
  57. 57.
    Lin, J. K. and Tsai, S. H. (1999) Chemoprevention of cancer and cardiovascular disease by resveratrol. Proc. Natl. Sci. Counc. Repub. China B 203, 99–106.Google Scholar
  58. 58.
    Dobsak, P., Courderot-Masuyer, C., Zeller, M., Vergely, C., Laubriet, A., Assem, M., et al. (1999) Antioxidative properties of pyruvate and protection of the ischemic rat heart during cardioplegia. J. Cardiovasc. Pharmacol. 34, 651–659.PubMedGoogle Scholar
  59. 59.
    Chahine, R. and Feng, J. (1998) Protective effects of Taurine against reperfusion-induced arrhythmias in isolated ischemic rat heart. Arzneimittelforschung 48, 360–364.PubMedGoogle Scholar
  60. 60.
    Reiter, R. J., Tan, D. X., Qi, W., Manchester, L. C., Karbownik, M., and Calvo, J. R. (2000) Pharmacology and physiology of melatonin in the reduction of the oxidative stress in vivo. Biol. Signals Recept. 9, 160–171.PubMedGoogle Scholar
  61. 61.
    Rimm, E. B., Willett, W. C., Hu, F. B., Sampson, L., Colditz, G. A., Manson, J. E., et al. (1998) Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 279, 359–364.PubMedGoogle Scholar
  62. 62.
    Barandier, C., Tanguy, S., Pucheu, S., Boucher, F., and de Leiris, J. (1999) Effect of antioxidant trace elements on the response of cardiac tissue to oxidative stress. Ann. N. Y. Acad. Sci. 874, 138–155.PubMedGoogle Scholar
  63. 63.
    de Lorgeril, M., Salen, P., Accominotti, M., Cadau, M., Steghens, J. P., Boucher, F., et al. (2001) Dietary and blood antioxidants in patients with chronic heart failure. Insights into the potential importance of selenium in heart failure. Eur. J. Heart. Failure 3, 661–669.Google Scholar
  64. 64.
    Munzel, T. and Keaney, J. F. Jr. (2001) Are ACE inhibitors a “magic bullet” against oxidative stress? Circulation 104, 1571–1574.PubMedGoogle Scholar
  65. 65.
    Tamba, M. and Torreggiani, A. (2000) Free radical scavenging and copper chelation: a potentially beneficial action of captopril. Free Rad. Res. 32, 199–211.Google Scholar
  66. 66.
    Feuerstein, G., Yue, T. L., Ma, X., and Ruffolo, R. R. (1998) Novel mechanisms in the treatment of heart failure: inhibition of oxygen radicals and apoptosis by carvedilol. Prog. Cardiovasc. Dis. 41, S17–24.PubMedGoogle Scholar
  67. 67.
    Roth, E. and Torok, B. (1991) Effect of the ultrashort-acting beta-blocker Brevibloc on free-radical-mediated injuries during the early reperfusion state. Basic Res. Cardiol. 86, 422–433.PubMedGoogle Scholar
  68. 68.
    Paroczai, M., Roth, E., Matos, G., Temes, G., Lantos, J., and Karpati, E. (1996) Effects of bisaramil on coronary-occlusion-reperfusion injury and free-radical-induced reactions. Pharmacol. Res. 33, 327–336.PubMedGoogle Scholar
  69. 69.
    Roth, E., Matos, G., Guarnieri, C., Papp, B., and Varga, J. (1995) Influence of the beta-blocker therapy on neutrophil superoxide generation and platelet aggregation in experimental myocardial ischemia and reflow. Acta Physiol. Hung. 83, 163–170.PubMedGoogle Scholar
  70. 70.
    Bhat, V. B. and Madyastha, K. M. (2001) Antioxidant and radical scavenging properties of 8-oxo derivatives of xanthine drugs pentoxifylline and lisofylline. Biochem. Biophys. Res. Commun. 288, 1212–1217.PubMedGoogle Scholar
  71. 71.
    Javadov, S. A., Lim, K. H., Kerr, P. M., Suleiman, M. S., Angelini, G. D., and Halestrap, A. P. (2000) Protection of hearts from reperfusion injury by propofol is associated with inhibition of the mitochondrial permeability transition. Cardiovasc. Res. 45, 360–369.PubMedGoogle Scholar
  72. 72.
    Ferreira, R., Burgos, M., Llesuy, S., Molteni, L., Milei, J., Flecha, B. G., et al. (1989) Reduction of reperfusion injury with mannitol cardioplegia. Ann. Thorac. Surg. 48, 77–83.PubMedGoogle Scholar
  73. 73.
    Xu, J., Chang, Y., Ouyang, B., Lu, Z., and Li, L. (1998) Influence of isoflurane and sevoflurane on metabolism of oxygen free radicals in cardiac valve replacement (abstract). Hunan. Yi. Ke. Da. Xue. Bao. 23, 489–491.Google Scholar
  74. 74.
    Kelly, G. S. (1998) Clinical applications of N-acetylcysteine. Altern. Med. Rev. 3, 114–127.PubMedGoogle Scholar
  75. 75.
    Marchetti, G., Lodola, E., Licciardello, L., and Colombo, A. (1999) Use of N-acetylcysteine in the management of coronary artery diseases. Cardiologia 44, 633–637.PubMedGoogle Scholar
  76. 76.
    Andrews, N. P., Prasad, A., and Quyyumi, A. A. (2001) N-acetylcysteine improves coronary and peripheral vascular function. J. Am. Coll. Cardiol. 37, 117–123.PubMedGoogle Scholar
  77. 77.
    Dage, R. C., Anderson, B. A., Mao, S. J., and Koerner, J. E. (1991) Probucol reduces myocardial dysfunction during reperfusion after short-term ischemia in rabbit heart. J. Cardiovasc. Pharmacol. 17, 158–165.PubMedGoogle Scholar
  78. 78.
    Horwitz, L. D., Fennessey, P. V., Shikes, R. H., and Kong, Y. (1994) Marked reduction in myocardial infarct size due to prolonged infusion of an antioxidant during reperfusion. Circulation 89, 1792–1801.PubMedGoogle Scholar
  79. 79.
    Miki, T., Cohen, M. V., and Downey, J. M. (1999) Failure of N-2-mercaptopropionyl glycine to reduce myocardial infarction after 3 days of reperfusion in rabbits. Basic Res. Cardiol. 94, 180–187.PubMedGoogle Scholar
  80. 80.
    Kinugawa, S., Tsutsui, H., Hayashidani, S., Ide, T., Suematsu, N., Satoh, S., et al. (2000) Treatment with dimethylthiourea prevents left ventricular remodeling and heart failure after experimental myocardial infarction in mice: Role of oxidative stress. Circ. Res. 87, 392–398.PubMedGoogle Scholar
  81. 81.
    Hashimoto, K., Minatoguchi, S., Hashimoto, Y., Wang, N., Qiu, X., Yamashita, K., et al. (2001) role of protein kinase C, KATP channels and DNA fragmentation in the infarct size reducing effects of the free radical scavenger T-0970. Clin. Exp. Pharmacol. Physiol. 28, 193–199.PubMedGoogle Scholar
  82. 82.
    McDonald, M. C., Zacharowski, K., Bowes, J., Cuzzocrea, S., and Thiemermann, C. (1999) Tempol reduces infarct size in rodent models of regional myocardial ischemia and reperfusion. Free Rad. Biol. Med. 27, 493–503.PubMedGoogle Scholar
  83. 83.
    Headrick, J. P., Armiger, L. C., and Willis, R. J. (1990) Behaviour of energy metabolites and effect of allopurinol in the “stunned” isovolumic rat heart. J. Mol. Cell. Cardiol. 22, 1107–1116.PubMedGoogle Scholar
  84. 84.
    Khatib, S. Y., Farah, H., and El-Migdadi, F. (2001) Allopurinol enhances adenine nucleotide levels and improves myocardial function in isolated hypoxic rat heart. Biochemistry (Mosc) 66, 328–333.Google Scholar
  85. 85.
    Clancy, R. R., McGaurn, S. A., Goin, J. E., Hirtz, D. G., Norwood, W. I., Gaynor, J. W., et al. (2001) Allopurinol neurocardiac protection trial in infants undergoing heart surgery using deep hypothermic circulatory arrest. Pediatrics 108, 61–70.PubMedGoogle Scholar
  86. 86.
    Soong, C. V., Young, I. S., Lightbody, J. H., Hood, J. M., Rowlands, B. J., Trimble, E. R., and BarrosD’Sa, A. A. (1994) Reduction of free radical generation minimises lower limb swelling following femoropopliteal bypass surgery. Eur. J. Vasc. Surg. 8, 435–440.PubMedGoogle Scholar
  87. 87.
    Cardillo, C., Kilcoyne, C. M., Cannon, R. O. 3rd, Quyyumi, A. A., and Panza, J. A. (1997) Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension 30, 57–63.PubMedGoogle Scholar
  88. 88.
    Aucamp, J., Gaspar, A., Hara, Y., and Apostolides, Z. (1997) Inhibition of xanthine oxidase by catechins from tea (Camellia sinensis). Anticancer Res. 17, 4381–4385.PubMedGoogle Scholar
  89. 89.
    de Cavanagh, E. M., Inserra, F., Toblli, J., Stella, I., Fraga, C. G., and Ferder, L. (2001) Enalapril attenuates oxidative stress in diabetic rats. Hypertension 38, 1130–1136.PubMedGoogle Scholar
  90. 90.
    Yusuf, S., Sleight, P., Pogue, J., Bosch, J., Davies, R., and Dagenais, G. (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N. Engl. J. Med. 342, 145–153.PubMedGoogle Scholar
  91. 91.
    Hink, U., Li, H., Mollnau, H., Oelze, M., Matheis, E., Hartmann, M., et al. (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ. Res. 88, E14–22.Google Scholar
  92. 92.
    Munzel, T., Li, H., Mollnau, H., Hink, U., Matheis, E., Hartmann, M., et al. (2000) Effects of long-term nitroglycerin treatment on endothelial nitric oxide synthase (NOS III) gene expression, NOS III-mediated superoxide production, and vascular NO bio-availability. Circ. Res. 86, E7–E12.PubMedGoogle Scholar
  93. 93.
    Heitzer, T., Finckh, B., Albers, S., Krohn, K., Kohlschutter, A., and Meinertz, T. (2001) Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients: Relation to parameters of oxidative stress. Free Rad. Biol. Med. 31, 53–61.PubMedGoogle Scholar
  94. 94.
    Heitzer, T., Krohn, K., Albers, S., and Meinertz, T. (2000) Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with Type II diabetes mellitus. Diabetologia 43, 1435–1438.PubMedGoogle Scholar
  95. 95.
    Heitzer, T., Brockhoff, C., Mayer, B., Warnholtz, A., Mollnau, H., Henne, S., et al. (2000) Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers: Evidence for a dysfunctional nitric oxide synthase. Circ. Res. 86, E36–E41.PubMedGoogle Scholar
  96. 96.
    Reddy, B. R., Wynne, J., Kloner, R. A., and Przyklenk, K. (1991) Pretreatment with the iron chelator desferrioxamine fails to provide sustained protection against myocardial ischaemia-reperfusion injury. Cardiovasc. Res. 25, 711–718.PubMedGoogle Scholar
  97. 97.
    Spencer, K. T., Lindower, P. D., Buettner, G. R., and Kerber, R. E. (1998) Transition metal chelators reduce directly measured myocardial free radical production during reperfusion. J. Cardiovasc. Pharmacol. 32, 343–348.PubMedGoogle Scholar
  98. 98.
    Bolli, R., Patel, B. S., Zhu, W. X., O’Neill, P. G., Hartley, C. J., Charlat, M. L., et al. (1987) The iron chelator desferrioxamine attenuates postischemic ventricular dysfunction. Am. J. Physiol. 253, H1372–1380.Google Scholar
  99. 99.
    Matthews, A. J., Vercellotti, G. M., Menchaca, H. J., Bloch, P. H., Michalek, V. N., Marker, P. H., et al. (1997) Iron and atherosclerosis: Inhibition by the iron chelator deferiprone (L1). J. Surg. Res. 73, 35–40.PubMedGoogle Scholar
  100. 100.
    Porreca, E., Ucchino, S., Di Febbo, C., Di Bartolomeo, N., Angelucci, D., Napolitano, A. M., et al. (1994) Antiproliferative effect of desferrioxamine on vascular smooth muscle cells in vitro and in vivo. Arterioscler. Thromb. 14, 299–304.PubMedGoogle Scholar
  101. 101.
    Duffy, S. J., Biegelsen, E. S., Holbrook, M., Russell, J. D., Gokce, N., Keaney, J. F. Jr., and Vita, J. A. (2001) Iron chelation improves endothelial function in patients with coronary artery disease. Circulation 103, 2799–2804.PubMedGoogle Scholar
  102. 102.
    Pepper, J. R., Mumby, S., and Gutteridge, J. M. (1994) Transient iron-overload with bleomycin-detectable iron present during cardiopulmonary bypass surgery. Free Rad. Res. 21, 53–58.Google Scholar
  103. 103.
    Menasche, P., Grousset, C., Gauduel, Y., Mouas, C., and Piwnica, A. (1988) A new concept of cardioplegic protection in cardiac surgery: iron chelation. Arch. Mal. Coeur Vaiss. 81, 811–816.PubMedGoogle Scholar
  104. 104.
    Menasche, P., Pasquier, C., Bellucci, S., Lorente, P., Jaillon, P., and Piwnica, A. (1988) Deferoxamine reduces neutrophil-mediated free radical production during cardiopulmonary bypass in man. J. Thorac. Cardiovasc. Surg. 96, 582–589.PubMedGoogle Scholar
  105. 105.
    Bel, A., Martinod, E., and Menasche, P. (1996) Cardioprotective effect of desferrioxamine. Acta Haematol. 95, 63–65.PubMedGoogle Scholar
  106. 106.
    Stamler, A., Wang, S. Y., Aquirre, D. E., Sellke, F. W., and Johnson R. G. (1996) Effects of pentastarch-deferoxamine conjugate on lung injury after cardiopulmonary bypass. Circulation 94, II358–II363.PubMedGoogle Scholar
  107. 107.
    Black, S. C. (2000) In vivo models of myocardial ischemia and reperfusion injury. Application to drug discovery and evaluation. J. Pharm. Toxicol. Meth. 43, 153–167.Google Scholar
  108. 108.
    Jordan, J. E., Zhao, Z. Q., and Vinten-Johansen, J. (1999) The role of neutrophils in myocardial ischemia-reperfusion injury. Cardiovasc. Res. 43, 860–878.PubMedGoogle Scholar
  109. 109.
    Hayashi, Y., Sawa, Y., Nishimura, M., Ichikawa, H., Kagisaki, K., Ohtake, S., et al. (2000) Clinical evaluation of leukocyte-depleted blood cardioplegia for pediatric open heart operation. Ann. Thorac. Surg. 69, 1914–1919.PubMedGoogle Scholar
  110. 110.
    Riley, R. D., Sato, H., Zhao, Z. Q., Thourani, V. H., Jordan, J. E., Fernandez, A. X., et al. (2000) Recombinant human complement C5a receptor antagonist reduces infarct size after surgical revascularization. J. Thorac. Cardiovasc. Surg. 120, 350–358.PubMedGoogle Scholar
  111. 111.
    Klein, H. H., Pich, S., Bohle, R. M., Lindert, S., Nebendahl, K., Buchwald, A., et al. (1988) Antiinflammatory agent BW 755 C in ischemic reperfused porcine hearts. J. Cardiovasc. Pharmacol. 12, 338–344.PubMedGoogle Scholar
  112. 112.
    Ravingerova, T., Styk, J., Tregerova, V., Pancza, D., Slezak, J., Tribulova, N., et al. (1991) Protective effect of 7-oxo-prostacyclin on myocardial function and metabolism during postischemic reperfusion and calcium paradox. Basic Res. Cardiol. 86, 245–253.PubMedGoogle Scholar
  113. 113.
    Rossoni, G., Manfredi, B., Colonna, V. D., Bernareggi, M., and Berti, F. (2001) The nitroderivative of aspirin, NCX 4016, reduces infarct size caused by myocardial ischemia-reperfusion in the anesthetized rat. J. Pharmacol. Exp. Ther. 297, 380–387.PubMedGoogle Scholar
  114. 114.
    Bouchard, J. F. and Lamontagne, D. (1999) Mechanisms of protection afforded by cyclooxygenase inhibitors to endothelial function against ischemic injury in rat isolated hearts. J. Cardiovasc. Pharmacol. 34, 755–763.PubMedGoogle Scholar
  115. 115.
    Buchwald, A., Klein, H. H., Lindert, S., Pich, S., Nebendahl, K., Wiegand, V., and Kreuzer, H. (1989) Effect of intracoronary superoxide dismutase on regional function in stunned myocardium. J. Cardiovasc. Pharmacol. 13, 258–264.PubMedGoogle Scholar
  116. 116.
    Ambrosio, G., Becker, L. C., Hutchins, G. M., Weisman, H. F., and Weisfeldt, M. L. (1986) Reduction in experimental infarct size by recombinant human superoxide dismutase: Insights into the pathophysiology of reperfusion injury. Circulation 74, 1424–1433.PubMedGoogle Scholar
  117. 117.
    Werns, S. W., Simpson, P. J., Mickelson, J. K., Shea, M. J., Pitt, B., and Lucchesi, B. R. (1988) Sustained limitation by superoxide dismutase of canine myocardial injury due to regional ischemia followed by reperfusion. J. Cardiovasc. Pharmacol. 11, 36–44.PubMedGoogle Scholar
  118. 118.
    Ambrosio, G., Zweier, J. L., and Becker, L. C. (1998) Apoptosis is prevented by administration of superoxide dismutase in dogs with reperfused myocardial infarction. Basic. Res. Cardiol. 93, 94–96.PubMedGoogle Scholar
  119. 119.
    Naslund, U., Haggmark, S., Johansson, G., Marklund, S. L., and Reiz, S. (1990) Limitation of myocardial infarct size by superoxide dismutase as an adjunct to reperfusion after different durations of coronary occlusion in the pig. Circ. Res. 66, 1294–1301.PubMedGoogle Scholar
  120. 120.
    Naslund, U., Haggmark, S., Johansson, G., Marklund, S. L., Reiz, S., and Oberg, A. (1986) Superoxide dismutase and catalase reduce infarct size in a porcine myocardial occlusion-reperfusion model. J. Mol. Cell. Cardiol. 18, 1077–1084.PubMedGoogle Scholar
  121. 121.
    Prasad, K., Chan, W. P., and Bharadwaj, B. (1996) Superoxide dismutase and catalase in protection of cardiopulmonary bypass-induced cardiac dysfunction and cellular injury. Can. J. Cardiol. 12, 1083–1091.PubMedGoogle Scholar
  122. 122.
    Tanaka, M., Richard, V. J., Murry, C. E., Jennings, R. B., and Reimer, K. A. (1993) Superoxide dismutase plus catalase therapy delays neither cell death nor the loss of the TTC reaction in experimental myocardial infarction in dogs. J. Mol. Cell. Cardiol. 25, 367–378.PubMedGoogle Scholar
  123. 123.
    Omar, B. A. and McCord, J. M. (1990) The cardioprotective effect of Mn-superoxide dismutase is lost at high doses in the postischemic isolated rabbit heart. Free Rad. Biol. Med. 9, 473–478.PubMedGoogle Scholar
  124. 124.
    Omar, B. A., Gad, N. M., Jordan, M. C., Striplin, S. P., Russell, W. J., Downey, J. M., et al. (1990) Cardioprotection by Cu,Zn-superoxide dismutase is lost at high doses in the reoxygenated heart. Free Rad. Biol. Med. 9, 465–471.PubMedGoogle Scholar
  125. 125.
    Flaherty, J. T., Pitt, B., Gruber, J. W., Heuser, R. R., Rothbaum, D. A., Burwell, L. R., et al. (1994) Recombinant human superoxide dismutase (h-SOD) fails to improve recovery of ventricular function in patients undergoing coronary angioplasty for acute myocardial infarction. Circulation 89, 1982–1991.PubMedGoogle Scholar
  126. 126.
    Black, S. C., Schasteen, C. S., Weiss, R. H., Riley, D. P., Driscoll, E. M., and Lucchesi, B. R. (1994) Inhibition of in vivo myocardial ischemic and reperfusion injury by a synthetic manganese-based superoxide dismutase mimetic. J. Pharm. Exp. Ther. 270, 1208–1215.Google Scholar
  127. 127.
    Hangaishi, M., Nakajima, H., Taguchi, J., Igarashi, R., Hoshino, J., Kurokawa, K., et al. (2001) Lecithinized Cu, Zn-superoxide dismutase limits the infarct size following ischemia-reperfusion injury in rat hearts in vivo. Biochem. Biophys. Res. Commun. 285, 1220–1225.PubMedGoogle Scholar
  128. 128.
    Suzuki, K., Sawa, Y., Ichikawa, H., Kaneda, Y., and Matsuda, H. (1999) Myocardial protection with endogenous overexpression of manganese superoxide dismutase. Ann. Thorac. Surg. 68, 1266–1271.PubMedGoogle Scholar
  129. 129.
    Li, G., Chen, Y., Saari, J. T., and Kang, Y. J. (1997) Catalase-overexpressing transgenic mouse heart is resistant to ischemia-reperfusion injury. Am. J. Physiol. 273, H1090–H1095.PubMedGoogle Scholar
  130. 130.
    Zhu, H. L., Stewart, A. S., Taylor, M. D., Vijayasarathy, C., Gardner, T. J., and Sweeney, H. L. (2000) Blocking free radical production via adenoviral gene transfer decreases cardiac ischemia-reperfusion injury. Mol. Ther. 2, 470–475.PubMedGoogle Scholar
  131. 131.
    Abunasra, H. J., Smolenski, R. T., Morrison, K., Yap, J., Sheppard, M. N., O’Brien, T., et al. (2001) Efficacy of adenoviral gene transfer with manganese superoxide dismutase and endothelial nitric oxide synthase in reducing ischemia and reperfusion injury. Eur. J. Cardiothorac. Surg. 20, 153–158.PubMedGoogle Scholar
  132. 132.
    Ho, Y. S., Magnenat, J. L., Gargano, M., and Cao, J. (1998) The nature of antioxidant defense mechanisms: A lesson from transgenic studies. Environ. Health Perspect. 106(S5), 1219–28.PubMedGoogle Scholar
  133. 133.
    Huang, T. T., Carlson, E. J., Raineri, I., Gillespie, A. M., Kozy, H., and Epstein, C., J. (1999) The use of transgenic and mutant mice to study oxygen free radical metabolism. Ann. N. Y. Acad. Sci. 893, 95–112.PubMedGoogle Scholar
  134. 134.
    Chen, Z., Siu, B., Ho, Y.S., Vincent, R., Chua, C. C., Hamdy, R. C., et al. (1998) Overexpression of MnSOD protects against myocardial ischemia/reperfusion injury in transgenic mice. J. Mol. Cell. Cardiol. 30, 2281–2289.PubMedGoogle Scholar
  135. 135.
    Kang, Y. J., Li, G., and Saari, J. T. (1999) Metallothionein inhibits ischemia-reperfusion injury in mouse heart. Am. J. Physiol. 276, H993–H997.PubMedGoogle Scholar
  136. 136.
    Horenstein, M. S., Vander Heide, R. S., and ĽEcuyer, T. J. (2000) Molecular basis of anthracyclin-induced cardiotoxicity and its prevention. Mol. Gen. Metab. 71, 436–444.Google Scholar
  137. 137.
    Mohamed, H. E., El-Swefy, S. E., and Hagar, H. H. (2000) The protective effect of glutathione administration on adriamycin-induced acute cardiac toxicity in rats. Pharmacol. Res. 42, 115–121.PubMedGoogle Scholar
  138. 138.
    Stathopoulos, G. P., Malamos, N. A., Dontas, I., Deliconstantinos, G., Perrea-Kotsareli, D., and Karayannacos, P. E. (1998) Inhibition of adriamycin cardiotoxicity by 5-fluorouracil: A potential free oxygen radical scavenger. Anticancer Res. 18, 4387–4392.PubMedGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2003

Authors and Affiliations

  • Elizabeth Roth
    • 1
  • Laszlo Hejjel
    • 2
  1. 1.Department of Experimental Surgery, Medical FacultyUniversity of PecsPecsHungary
  2. 2.Division of Cardiac Surgery, Heart Institute, Medical FacultyUniversity of PecsPecsHungary

Personalised recommendations