Inhibition of TNF-α reduces myocardial injury and proinflammatory pathways following ischemia-reperfusion in the dog

Qiuping Gu, Xiao Ping Yang, Pramod Bonde, Anthony DiPaula, Karen Fox-Talbot, Lewis Becker

Research output: Contribution to journalArticle

Abstract

We examined whether tumor necrosis factor-α (TNF-α) promotes postischemic inflammation and myocardial injury via activation of nuclear factor kappa B (NFκB) in an in vivo canine model. Isoflurane-anesthetized dogs underwent closed-chest balloon occlusion of the anterior descending coronary artery for 90 minutes, followed by reperfusion for 3 hours. Dogs randomly received a soluble TNF inhibitor (etanercept, 0.5 mg/kg intravenously) or saline before occlusion. Collateral blood flow and risk region size (RISK) were measured with radioactive microspheres, infarct size (INF) was measured by triphenyltetrazolium chloride staining, inflammation was measured by tissue myeloperoxidase (MPO) activity, intercellular adhesion molecular-1 (ICAM-1) messenger ribonucleic acid (mRNA) was measured by Northern blotting, and ICAM-1 protein expression was measured by Western blotting. NFκB activation was measured in nuclear extracts by electrophoretic mobility shift assays. INF/RISK was significantly smaller in the etanercept group than in the saline control group after adjusting for collateral flow (P <0.009 by analysis of covariance, mean reduction in INF/RISK = 40%, 0.32 ± 0.09 versus 0.53 ± 0.09). MPO activity, ICAM-1 mRNA and protein expression, and NFκB binding activity were all significantly reduced in the etanercept group. Administration of a soluble TNF-α inhibitor reduced NFκB activation, ICAM-1 upregulation, and myocardial injury following ischemia-reperfusion. TNF-α appears to play a significant role in vivo in the genesis of postischemic inflammation.

Original languageEnglish (US)
Pages (from-to)320-328
Number of pages9
JournalJournal of Cardiovascular Pharmacology
Volume48
Issue number6
DOIs
Publication statusPublished - Dec 2006

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Keywords

  • Cytokines
  • Etanercept
  • Infarction
  • Leukocytes
  • Nuclear factor κB
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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