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

Nancy C. Moss, Ru Hang Tang, Monte Willis, William E. Stansfield, Albert S. Baldwin, Craig H. Selzman

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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-κB 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-α 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-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.

Original languageEnglish (US)
Pages (from-to)1274-1279
Number of pages6
JournalJournal of Thoracic and Cardiovascular Surgery
Volume136
Issue number5
DOIs
StatePublished - Nov 1 2008
Externally publishedYes

Fingerprint

NF-kappa B
Reperfusion
Phosphotransferases
Proteasome Endopeptidase Complex
Myocardial Ischemia
Ischemia
Arteries
Myocardial Reperfusion Injury
Protective Agents
Myocardial Reperfusion
Proteasome Inhibitors
Acute Coronary Syndrome
Nuclear Proteins
Reperfusion Injury
Inbred C57BL Mouse
Thoracic Surgery
Interleukin-6
Tumor Necrosis Factor-alpha
Western Blotting
Enzyme-Linked Immunosorbent Assay

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Pulmonary and Respiratory Medicine

Cite this

Inhibitory kappa B kinase-β is a target for specific nuclear factor kappa B-mediated delayed cardioprotection. / Moss, Nancy C.; Tang, Ru Hang; Willis, Monte; Stansfield, William E.; Baldwin, Albert S.; Selzman, Craig H.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 136, No. 5, 01.11.2008, p. 1274-1279.

Research output: Contribution to journalArticle

Moss, Nancy C. ; Tang, Ru Hang ; Willis, Monte ; Stansfield, William E. ; Baldwin, Albert S. ; Selzman, Craig H. / Inhibitory kappa B kinase-β is a target for specific nuclear factor kappa B-mediated delayed cardioprotection. In: Journal of Thoracic and Cardiovascular Surgery. 2008 ; Vol. 136, No. 5. pp. 1274-1279.
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