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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/H2248    most recent 00776.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Moss, N. C. Articles by Selzman, C. H. Search for Related Content PubMed PubMed Citation Articles by Moss, N. C. Articles by Selzman, C. H.

IKK inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury

Departments of ¹Surgery and ²Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina

Submitted 5 July 2007 ; accepted in final form 2 August 2007

Despite years of experimental and clinical research, myocardial ischemia-reperfusion (IR) remains an important cause of cardiac morbidity and mortality. The transcription factor nuclear factor-B (NF-B) has been implicated as a key mediator of reperfusion injury. Activation of NF-B is dependent upon the phosphorylation of its inhibitor, IB, by the specific inhibitory B kinase (IKK) subunit, IKK. We hypothesized that specific antagonism of the NF-B inflammatory pathway through IKK inhibition reduces acute myocardial damage following IR injury. C57BL/6 mice underwent left anterior descending (LAD) artery ligation and release in an experimental model of acute IR. Bay 65-1942, an ATP-competitive inhibitor that selectively targets IKK kinase activity, was administered intraperitoneally either prior to ischemia, at reperfusion, or 2 h after reperfusion. Compared with untreated animals, mice treated with IKK inhibition had significant reduction in left ventricular infarct size. Cardiac function was also preserved following pretreatment with IKK inhibition. These findings were further associated with decreased expression of phosphorylated IB and phosphorylated p65 in myocardial tissue. In addition, IKK inhibition decreased serum levels of TNF- and IL-6, two prototypical downstream effectors of NF-B activity. These results demonstrate that specific IKK inhibition can provide both acute and delayed cardioprotection and offers a clinically accessible target for preventing cardiac injury following IR.

inhibitory B kinase-; myocardial infarction; nuclear factor-B

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