Inhibition of IκB phosphorylation in cardiomyocytes attenuates myocardial ischemia/reperfusion injury

Abstract

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 IκB phosphorylation blockade in a rat myocardial ischemia/reperfusion injury model. Methods and results: IMD-0354 inhibited phosphorylation of IκBα and nuclear translocation of nuclear factor-kappa B (NF-κB) induced by tumor necrosis factor-α (TNF-α) in cultured cardiomyocytes. TNF-α-induced production of interleukin-1β 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%; PPConclusions: Inhibition of nuclear translocation of NF-κB by IκBα 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.