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

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 depend...

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Bibliographic Details
Published in:American journal of physiology. Heart and circulatory physiology 2007-10, Vol.293 (4), p.H2248
Main Authors: Moss, Nancy C, Stansfield, William E, Willis, Monte S, Tang, Ru-Hang, Selzman, Craig H
Format: Article
Language:English
Subjects:
Heart attacks
Injuries
Kinases
Medical research
Morbidity
Rodents
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Summary: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, I...Bα, by the specific inhibitory ...B kinase (IKK) subunit, IKKβ. We hypothesized that specific antagonism of the NF-...B inflammatory pathway through IKKβ 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 IKKβ kinase activity, was administered intraperitoneally either prior to ischemia, at reperfusion, or 2 h after reperfusion. Compared with untreated animals, mice treated with IKKβ inhibition had significant reduction in left ventricular infarct size. Cardiac function was also preserved following pretreatment with IKKβ inhibition. These findings were further associated with decreased expression of phosphorylated I...Ba and phosphorylated p65 in myocardial tissue. In addition, IKKβ inhibition decreased serum levels of TNF-α and IL-6, two prototypical downstream effectors of NF-...B activity. These results demonstrate that specific IKKβ inhibition can provide both acute and delayed cardioprotection and offers a clinically accessible target for preventing cardiac injury following IR. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:0363-6135
1522-1539