Journal
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
Volume 48, Issue 6, Pages 320-328Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.fjc.0000250079.46526.38
Keywords
cytokines; leukocytes; infarction; tumor necrosis factor-alpha; nuclear factor kappa B; etanercept
Funding
- NHLBI NIH HHS [P01 HL065608] Funding Source: Medline
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We examined whether tumor necrosis factor-alpha (TNF-alpha) promotes postischemic inflammation and myocardial injury via activation of nuclear factor kappa B (NF kappa B) 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 mycloperoxidase (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. NF kappa B activation was measured in nuclear extracts by electrophoretlic 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 NF kappa B binding activity were all significantly reduced in the etanercept group. Administration of a soluble TNF-a inhibitor reduced NF kappa B activation, ICAM-1 upregulation, and myocardial injury following ischemia-reperfusion. TNF-a appears to play a significant role in vivo in the genesis of postischemic inflammation.
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