Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 586, Issue 1-3, Pages 251-258Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2008.02.038
Keywords
myocardial infarction; ischemia/reperfusion; NF-kappa B; cardioprotection; dimethyl fumarate
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Persistent Nuclear Factor-kappa B (NF-kappa B) activation is hypothesized to contribute to myocardial injuries following ischemia-reperfusion. Because inhibition or control of NF-kappa B signaling in the heart probably confers cardioprotection, we determined the potency of the NF-kappa B inhibitor dimethyl fumarate (DMF) in cardiovascular cells, and determined whether administration of DMF translates into beneficial effects in an animal model of myocardial infarction. In rat heart endothelial cells (RHEC), we analysed inhibitory effects of DMF on NF-kappa B using shift assay and immunohistofluorescence. In in vivo experiments, male Sprague Dawley rats undergoing left coronary artery occlusion for 45 min received either DMF (10 mg/kg body weight) or vehicle 90 min before ischemia as well as immediately before ischemia. After 120 min of reperfusion, the hearts were stained with phthalocyanine blue dye and triphenyltetrazolium chloride. Additionally, acute hemodynamic and electrophysiologic effects of DMF were determined in dose-response experiments in isolated perfused rat hearts. DMF inhibited TNF-alpha-induced nuclear entry of NF-kappa B in RHEC. In in vivo experiments, myocardial infarct size was significantly smaller in rats that had received DMF (20.7%+/- 9.7% in % of risk area; n = 17) than in control rats (28.2%+/- 6.2%; n = 15). Dose-response experiments in isolated perfused rat hearts excluded acute hemodynamic or electrophysiologic effects as mechanisms for the effects of DMF. DMF inhibits nuclear entry of NF-kappa B in RHEC and reduces myocardial infarct size after ischemia and reperfusion in rats in vivo. There was no indication that the beneficial effects of DMF were due to acute hemodynamic or electrophysiologic influences. (c) 2008 Elsevier B.V. All rights reserved.
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