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| Inhibitory kappa B kinase-β (IKKβ) is a target for specific NF-κB-mediated delayed cardioprotection |
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Nancy C. Moss, Bill Stansfield, Ruhang Tang, Craig H. Selzman; Surgery, University of North Carolina, Chapel Hill, NC Objective: Myocardial ischemia-reperfusion (IR) injury associated with cardiac surgery and acute coronary syndromes remains a vexing problem. Translating experimental strategies that most frequently deliver protective agents prior to the ischemic insult significantly limit their clinical applicability. We have previously reported the importance of the transcription factor Nuclear Factor kappa B (NF-κB) in regulating myocardial IR. To model a more relevant therapeutic strategy, we targeted two proteins in the NF-κB pathway, Inhibitory Kappa B Kinase β (IKKβ) and the 26S cardiac proteasome, to determine their cardioprotective effects when delivered during reperfusion. Methods: 10 week-old C47BL6 mice underwent thoracotomy, left anterior descending artery (LAD) occlusion for 30 minutes, and release. An IKKβ inhibitor (Bay 65-1942), a proteasome inhibitor (PS-519), or normal saline vehicle was administered intraperitoneally at LAD release. Infarct size, analyzed 24 hours after injury with TTC staining, was expressed as percent area at risk. Pressure-volume loops were recorded 3 days after injury for functional analysis. A third subgroup was sacrificed one hour after injury to examine protein expression in heart homogenates and serum by western blot and ELISA respectively. Results: Vehicle mice suffered larger infarcts than sham animals (vehicle: 70.65% +/- 3.41, sham: 5.79% +/- 3.43, p<0.05). IKKβ and proteasome inhibition significantly attenuated infarct size (IKKβ: 42.70 % +/- 7.55, PS-519: 44.57 % +/- 3.81, p<0.05 compared with vehicle) and preserved ejection fraction compared to vehicle groups. When delivered even 2 hours after reperfusion, mice treated with IKKβ inhibition, but not PS-519, still had decreased infarct size. Finally, successful inhibition of the active NF-κB subunit, phosphorylated-p65, as well as decreased expression of IL-6 and TNFα occurred in mice given the IKKβ inhibitor, but not those with proteasome inhibition. Conclusion: Although IKKβ and proteasome inhibition at reperfusion attenuated infarct size and preserved function following acute IR, only IKKβ inhibition provides cardioprotection through specific suppression of NF-κB signaling. This feature of highly targeted NF-κB inhibition might account for its delayed protective effects and provide a clinically relevant option for treating myocardial IR associated with unknown periods of ischemia and reperfusion as seen in cardiac surgery and acute coronary syndromes. Back to 88th Annual Meeting Back to Program Outline |
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