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
| Autor: | Francesco Squadrito, Stefano Ceccarelli, Giovanni Squadrito, Giuseppe M. Campo, Domenico Cucinotta, Domenica Altavilla, Mariarita Arlotta, Maria Miano, Marcella Ferlito, Barbara Deodato, Letteria Minutoli, Achille P. Caputi, Antonino Saitta, Michelangelo Tringali |
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| Rok vydání: | 2000 |
| Předmět: |
Male
Cytoplasm medicine.medical_specialty Necrosis Physiology medicine.medical_treatment Ischemia Myocardial Reperfusion Injury medicine.disease_cause Antioxidants Rats Sprague-Dawley Lipid peroxidation chemistry.chemical_compound Reperfusion therapy Physiology (medical) Internal medicine medicine Animals Vitamin E Benzofurans Inflammation Analysis of Variance Pancreatic Elastase Hydroxyl Radical Reverse Transcriptase Polymerase Chain Reaction Superoxide Dismutase business.industry Myocardium NF-kappa B Intercellular Adhesion Molecule-1 Malondialdehyde medicine.disease Immunohistochemistry Rats Oxidative Stress Endocrinology chemistry Immunology RNA I-kappa B Proteins Lipid Peroxidation medicine.symptom Cardiology and Cardiovascular Medicine business Reperfusion injury Oxidative stress |
| Zdroj: | Cardiovascular Research. 47:515-528 |
| ISSN: | 0008-6363 |
| DOI: | 10.1016/s0008-6363(00)00124-3 |
| Popis: | 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.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 (OHz.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.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.Our data suggest that IRFI 042 is cardioprotective during myocardial infarction by limiting reperfusion-induced oxidative stress and by halting the inflammatory response. |
| Databáze: | OpenAIRE |
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