期刊
CARDIOVASCULAR RESEARCH
卷 63, 期 1, 页码 51-59出版社
OXFORD UNIV PRESS
DOI: 10.1016/j.cardiores.2004.03.002
关键词
myocardial infarction; reperfusion injury; nuclear factor-kappaB; cytokine; chemokine; cardiomyocyte
objective: Reperfusion injury is related closely to inflammatory reactions such as activation of inflammatory cells and expression of cytotoxic cytokines. We investigated the efficacy of IkappaB phosphorylation blockade in a rat myocardial ischemia/reperfusion injury model. Methods and results: IMD-0354 inhibited phosphorylation of IkappaBalpha and nuclear translocation of nuclear factor-kappa B (NF-kappaB) induced by turner necrosis factor-alpha (TNF-alpha) in cultured cardiomyocytes. TNF-alpha-induced production of interleukin-lbeta and monocyte chemoattractant protein-1 from Cultured cardiomyocytes was reduced significantly by IMD-0354. Transient left coronary artery occlusion (30 min) and reperfusion (24 h) were carried out in Sprague-Dawley rats. IMD-0354 (1, 5, 10 mg/kg) was injected intraperitoneally 5 min before the start of reperfusion. Treatment with IMD-0354 resulted in a significant dose-dependent reduction of the infarction area/area at risk ratio (vehicle, 47.0 +/- 3.4%; 10 mg/kg of IMD-0354, 19.4 +/- 4.0%; P < 0.01) and the preservation of fractional shortening ratio (vehicle, 25.0 +/- 1.5%; 10 mg/kg of IMD-0354. 42.3 +/- 1.7%; P < 0.01). Histological analysis showed that accumulation of polymorphonuclear neutrophils in the area at risk was decreased significantly. Conclusions: Inhibition of nuclear translocation of NF-kappaB by IkappaBalpha phosphorylation blockade could provide an effective approach to attenuation of ischemia/reperfusion injury. The cardioprotective effects of IMD-0354 include not only reduction of harmful neutrophil accumulation in myocardium but also inhibition of harmful cytokine and chemokine production by cardiomyocytes. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
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