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Cardiovascular Research 2004 63(1):51-59; doi:10.1016/j.cardiores.2004.03.002
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Inhibition of I{kappa}B phosphorylation in cardiomyocytes attenuates myocardial ischemia/reperfusion injury

Yasuyuki Onaia, Jun-ichi Suzukia, Tsunekazu Kakutaa, Yasuhiro Maejimaa, Go Haraguchia, Hiroshi Fukasawab, Susumu Mutob, Akiko Itaib and Mitsuaki Isobe*,a

aDepartment of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
bMedical Molecular Design, Inc., 5-24-5 Hongo, Bunkyo, Tokyo, Japan

*Corresponding author. Tel.: +81-3-5803-5951; fax: +81-3-5803-0238. Email address: isobemi.cvm{at}tmd.ac.jp

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 I{kappa}B phosphorylation blockade in a rat myocardial ischemia/reperfusion injury model. Methods and results: IMD-0354 inhibited phosphorylation of I{kappa}B{alpha} and nuclear translocation of nuclear factor-kappa B (NF-{kappa}B) induced by tumor necrosis factor-{alpha} (TNF-{alpha}) in cultured cardiomyocytes. TNF-{alpha}-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%; 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-{kappa}B by I{kappa}B{alpha} 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.

KEYWORDS Myocardial infarction; Reperfusion injury; Nuclear factor-kappaB; Cytokine; Chemokine; Cardiomyocyte

Time for primary review 28 days


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