Inhibitory kappa B kinase-beta is a target for specific nuclear factor kappa B-mediated delayed cardioprotection.
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-kappaB pathway, inhibitory kappa B kinase-beta, 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-beta 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-beta 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-alpha levels occurred in mice given the inhibitory kappa B kinase-beta inhibitor, but not in mice with proteasome inhibition.


CONCLUSIONS
Although inhibitory kappa B kinase-beta and proteasome inhibition at reperfusion attenuated infarct size after acute ischemia/reperfusion, only inhibitory kappa B kinase-beta inhibition provided cardioprotection through specific suppression of nuclear factor-kappaB signaling. This feature of highly targeted nuclear factor-kappaB 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.
Moss
Nancy C
NC
Department of Surgery, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Tang
Ru-Hang
RH
Willis
Monte
M
Stansfield
William E
WE
Baldwin
Albert S
AS
Selzman
Craig H
CH
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D000818:Animals; D052279:Creatine Kinase, MB Form / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D006352:Heart Ventricles / Q000737:chemistry; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016328:NF-kappa B / Q000032:analysis; D011506:Proteins / Q000032:analysis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D015850:Interleukin-6; D016328:NF-kappa B; C411422:PS519; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; D052279:Creatine Kinase, MB Form; D000111:Acetylcysteine