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

AbstractBACKGROUND:
Nuclear factor-kappaB (NF-kappaB) 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-kappaB 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&z.ccirf;) 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-kappaB activation and the inhibitory protein of NF-kappaB, I-kappaBalpha, 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-kappaB activation was also evident at 0.5 h of reperfusion and reached its maximum at 2 h of reperfusion. I-kappaBalpha 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-kappaB, 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.
AuthorsD Altavilla, B Deodato, G M Campo, M Arlotta, M Miano, G Squadrito, A Saitta, D Cucinotta, S Ceccarelli, M Ferlito, M Tringali, L Minutoli, A P Caputi, F Squadrito
JournalCardiovascular research (Cardiovasc Res) Vol. 47 Issue 3 Pg. 515-28 (Aug 18 2000) ISSN: 0008-6363 [Print] England
PMID10963724 (Publication Type: Journal Article)
Chemical References
  • Antioxidants
  • Benzofurans
  • I-kappa B Proteins
  • IRFI 042
  • NF-kappa B
  • Intercellular Adhesion Molecule-1
  • Vitamin E
  • Hydroxyl Radical
  • RNA
  • Superoxide Dismutase
  • Pancreatic Elastase
Topics
  • Analysis of Variance
  • Animals
  • Antioxidants (therapeutic use)
  • Benzofurans (chemistry, pharmacology)
  • Cytoplasm (metabolism)
  • Hydroxyl Radical (analysis)
  • I-kappa B Proteins (metabolism)
  • Immunohistochemistry
  • Inflammation
  • Intercellular Adhesion Molecule-1 (analysis, genetics)
  • Lipid Peroxidation (drug effects)
  • Male
  • Myocardial Reperfusion Injury (drug therapy, immunology, metabolism)
  • Myocardium (chemistry, metabolism)
  • NF-kappa B (metabolism)
  • Oxidative Stress (drug effects)
  • Pancreatic Elastase (analysis)
  • RNA (analysis)
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Superoxide Dismutase (analysis)
  • Vitamin E (analysis, blood)

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