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• W2149000466 abstract "ObjectiveMyocardial 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-κB pathway, inhibitory kappa B kinase-β, and 26S cardiac proteasome to determine their cardioprotective effects when delivered during reperfusion.MethodsC57BL/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.ResultsInhibitory 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-α levels occurred in mice given the inhibitory kappa B kinase-β inhibitor, but not in mice with proteasome inhibition.ConclusionAlthough 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-κB signaling. This feature of highly targeted nuclear factor-κB 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. 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-κB pathway, inhibitory kappa B kinase-β, and 26S cardiac proteasome to determine their cardioprotective effects when delivered during reperfusion. 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. 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-α levels occurred in mice given the inhibitory kappa B kinase-β inhibitor, but not in mice with proteasome inhibition. 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-κB signaling. This feature of highly targeted nuclear factor-κB 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." @default.
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• W2149000466 date "2008-11-01" @default.
• W2149000466 modified "2023-10-13" @default.
• W2149000466 title "Inhibitory kappa B kinase-β is a target for specific nuclear factor kappa B-mediated delayed cardioprotection" @default.
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• W2149000466 doi "https://doi.org/10.1016/j.jtcvs.2008.07.041" @default.
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