IRFI 042, a novel dual vitamin E-like antioxidant, inhibits activation of nuclear factor-κB and reduces the inflammatory response in myocardial ischemia-reperfusion injury

Domenica Altavilla, Barbara Deodato, Giuseppe M. Campo, Mariarita Arlotta, Maria Miano, Giovanni Squadrito, Antonino Saitta, Domenico Cucinotta, Stefano Ceccarelli, Marcella Ferlito, Michelangelo Tringali, Letteria Minutoli, Achille P. Caputi, Francesco Squadrito

Research output: Contribution to journalArticle

Abstract

Background: Nuclear factor-κB (NF-κB) is a ubiquitous rapid response transcription factor involved in inflammatory reactions which exerts its effect by expressing cytokines, chemokines, and cell adhesion molecules. Oxidative stress causes NF-κB activation. IRFI 042 is a novel dual vitamin E-like antioxidant and we, therefore, investigated its ability to protect the heart from oxidative stress and to halt the inflammatory response in a model of myocardial ischaemia-reperfusion injury. Methods: Anaesthetized rats were subjected to total occlusion (45 min) of the left main coronary artery followed by 5-h reperfusion (MI/R). Sham myocardial ischaemia rats (sham- operated rats) were used as controls. Myocardial necrosis, cardiac output, cardiac and plasma vitamin E levels, myocardial malondialdehyde (MAL), cardiac SOD activity and elastase content (an index of leukocyte infiltration), hydroxyl radical (OH) formation, cardiac amount of mRNA codifying for ICAM-1 (evaluated by the means of reverse transcriptase polymerase chain reaction) and ICAM-1 immunostaining in the at-risk myocardium were investigated. NF-κB activation and the inhibitory protein of NF-κB, I-κBα, were also studied in at-risk myocardium by using electrophoretic mobility shift assay (EMSA) and Western blot analysis, respectively. Results: The ischaemia-reperfusion model produced wide heart necrosis (area at risk-necrotic area = 52 ± 5%; necrotic area-left ventricle = 28 ± 3%), increased cardiac MAL, an index of lipid peroxidation (area at risk = 62.5 ± 3.9 nmol/g tissue; necrotic area = 80.3 ± 5.1 nmol/g tissue), induced tissue neutrophil infiltration, and caused a marked decrease in endogenous antioxidants. Furthermore, myocardial ischaemia plus reperfusion caused in the area at risk peak message for ICAM-1 at 3 h of reperfusion and increased cardiac ICAM-1 immunostaining at 5 h of reperfusion. NF-κB activation was also evident at 0.5 h of reperfusion and reached its maximum at 2 h of reperfusion. I-κBα was markedly decreased at 45 min of occlusion; peak reduction was observed at 1 h of reperfusion and thereafter it was gradually restored. Intraperitoneal administration of IRFI 042 (5, 10, 20 mg/kg, 5 min after reperfusion) reduced myocardial necrosis expressed as a percentage either of the area at risk (18 ± 4%) or the total left ventricle (11 ± 2%), and improved cardiac output. This treatment also limited membrane lipid peroxidation in the area at risk (MAL = 14.3 ± 2.5 nmol/g tissue) and in the necrotic area (MAL = 26.5 ± 3.7 nmol/g tissue), restored the endogenous antioxidants vitamin E and superoxide dismutase, and inhibited detrimental hydroxyl radical formation. Finally, IRFI 042 blocked the activation of NF-κB, reduced cardiac ICAM-1 expression, and blunted tissue elastase content, an index of leukocytes accumulation at the site of injury. Conclusions: Our data suggest that IRFI 042 is cardioprotective during myocardial infarction by limiting reperfusion-induced oxidative stress and by halting the inflammatory response. (C) 2000 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)515-528
Number of pages14
JournalCardiovascular research
Volume47
Issue number3
DOIs
StatePublished - Aug 18 2000

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Keywords

  • Free radicals
  • Hemodynamics
  • Infection/inflammation
  • Ischaemia
  • Necrosis
  • Reperfusion

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Altavilla, D., Deodato, B., Campo, G. M., Arlotta, M., Miano, M., Squadrito, G., Saitta, A., Cucinotta, D., Ceccarelli, S., Ferlito, M., Tringali, M., Minutoli, L., Caputi, A. P., & Squadrito, F. (2000). IRFI 042, a novel dual vitamin E-like antioxidant, inhibits activation of nuclear factor-κB and reduces the inflammatory response in myocardial ischemia-reperfusion injury. Cardiovascular research, 47(3), 515-528. https://doi.org/10.1016/S0008-6363(00)00124-3