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J Thorac Cardiovasc Surg 2008;136:1274-1279
© 2008 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Inhibitory kappa B kinase-β is a target for specific nuclear factor kappa B-mediated delayed cardioprotection

^a Department of Surgery, University of North Carolina, Chapel Hill, North Carolina
^b Department of Pathology, University of North Carolina, Chapel Hill, North Carolina
^c Department of Biology, University of North Carolina, Chapel Hill, North Carolina

Received for publication April 1, 2008; revisions received June 25, 2008; accepted for publication July 26, 2008.

^_* Address for reprints: Craig H. Selzman, MD, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, 3040 Burnett-Womack Bldg, CB 7065, Chapel Hill, NC 27599-7065. (Email: Selzman{at}med.unc.edu).

Objective: Myocardial ischemia/reperfusion injury remains a vexing problem. Translating experimental strategies that deliver protective agents before the ischemic insult limits clinical applicability. We targeted 2 proteins in the nuclear factor-B pathway, inhibitory kappa B kinase-β, and 26S cardiac proteasome to determine their cardioprotective effects when delivered during reperfusion.

Methods: C57BL/6 mice underwent left anterior descending artery occlusion for 30 minutes. An inhibitory kappa B kinase-β inhibitor (Compound A), a proteasome inhibitor (PS-519), or vehicle was administered at left anterior descending artery release or 2 hours afterward. Infarct size was analyzed 24 hours later. Pressure-volume loops were performed at 72 hours. Serum and left ventricular tissue were collected 1 hour after injury to examine protein expression by enzyme-linked immunosorbent assay and Western blot.

Results: Inhibitory kappa B kinase-β and proteasome inhibition significantly attenuated infarct size and preserved ejection fraction compared with the vehicle groups. When delivered even 2 hours after reperfusion, Compound A, but not PS-519, still decreased infarct size in mice. Finally, when delivered at reperfusion, successful inhibition of phosphorylated-p65 and decreased interleukin-6 and tumor necrosis factor- levels occurred in mice given the inhibitory kappa B kinase-β inhibitor, but not in mice with proteasome inhibition.

Conclusion: Although inhibitory kappa B kinase-β and proteasome inhibition at reperfusion attenuated infarct size after acute ischemia/reperfusion, only inhibitory kappa B kinase-β inhibition provided cardioprotection through specific suppression of nuclear factor-B signaling. This feature of highly targeted nuclear factor-B inhibition might account for its delayed protective effects, providing a clinically relevant option for treating myocardial ischemia/reperfusion associated with unknown periods of ischemia and reperfusion as seen in cardiac surgery and acute coronary syndromes.

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