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Absence of Inducible Nitric Oxide Synthase Reduces Myocardial Damage During Ischemia Reperfusion in Streptozotocin-Induced Hyperglycemic Mice

  1. Raffaele Marfella12,
  2. Clara Di Filippo23,
  3. Katherine Esposito14,
  4. Francesco Nappo1,
  5. Elena Piegari3,
  6. Salvatore Cuzzocrea4,
  7. Liberato Berrino23,
  8. Francesco Rossi23,
  9. Dario Giugliano12 and
  10. Michele D’Amico23
  1. 1Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy
  2. 2“Centro di Eccellenza Cardiovascolare,” Second University of Naples, Naples, Italy
  3. 3Department of Experimental Medicine, Second University of Naples, Naples, Italy
  4. 4Department of Pharmacology, University of Messina, Messina, Italy
  1. Address correspondence and reprint requests to Raffaele Marfella, Via Emilio Scaglione 141, 80145 Napoli, Italy. E-mail: raffaele.marfella{at}unina2.it

Abstract

We investigated the role of inducible nitric oxide synthase (iNOS) on ischemic myocardial damage and angiogenic process in genetically deficient iNOS (iNOS−/−) mice and wild-type littermates (iNOS+/+), with and without streptozotocin-induced (70 mg/kg intravenously) diabetes. After ischemia (25 min) and reperfusion (120 min), both iNOS+/+ and iNOS−/− diabetic mice (blood glucose 22 mmol/l) had myocardial infarct size greater than their respective nondiabetic littermates (P < 0.01). Myocardial infarct size (P < 0.05), apoptotic index (P < 0.005), and tissue levels of tumor necrosis factor (P < 0.01), interleukin-6 (P < 0.01), and interleukin-18 (P < 0.01) were higher in nondiabetic iNOS−/− mice compared with nondiabetic iNOS+/+ mice. As compared with diabetic iNOS−/− mice, diabetic iNOS+/+ mice showed a greater infarct size (P < 0.01) associated with the highest tissue levels of nitrotyrosine and proinflammatory cytokines, as well as apoptosis. The beneficial role of iNOS in modulating defensive responses against ischemia/reperfusion injury seems to be abolished in diabetic mice.

Footnotes

  • R.M. and C.D.F. contributed equally to this work.

    • Accepted October 23, 2003.
    • Received July 10, 2003.
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