IKKβ 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-kappa B (NF-kappa B) has been implicated as a key mediator of reperfusion injury. Activation of NF-kappa B is dependent upon the phosphorylation of its inhibitor, I kappa B alpha, by the specific inhibitory kappa B kinase (IKK) subunit, IKK beta. We hypothesized that specific antagonism of the NF-kappa B inflammatory pathway through IKK beta 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 beta kinase activity, was administered intraperitoneally either prior to ischemia, at reperfusion, or 2 h after reperfusion. Compared with untreated animals, mice treated with IKK beta inhibition had significant reduction in left ventricular infarct size. Cardiac function was also preserved following pretreatment with IKK beta inhibition. These findings were further associated with decreased expression of phosphorylated I kappa B alpha and phosphorylated p65 in myocardial tissue. In addition, IKK beta inhibition decreased serum levels of TNF-alpha and IL-6, two prototypical downstream effectors of NF-kappa B activity. These results demonstrate that specific IKK beta inhibition can provide both acute and delayed cardioprotection and offers a clinically accessible target for preventing cardiac injury following IR.