Role of TNF-alpha-induced reactive oxygen species in endothelial dysfunction during reperfusion injury

Xue Gao, Hanrui Zhang, Souad Belmadani, Junxi Wu, Xiangbin Xu, Howard Elford, Barry J. Potter, Cuihua Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Gao X, Zhang H, Belmadani S, Wu J, Xu X, Elford H, Potter BJ, Zhang C. Role of TNF-alpha-induced reactive oxygen species in endothelial dysfunction during reperfusion injury. Am J Physiol Heart Circ Physiol 295: H2242-H2249, 2008. First published October 10, 2008; doi: 10.1152/ajpheart.00587.2008. We hypothesized that neutralization of TNF-alpha at the time of reperfusion exerts a salubrious role on endothelial function and reduces the production of reactive oxygen species. We employed a mouse model of myocardial ischemia-reperfusion (I/R, 30 min/90 min) and administered TNF-alpha neutralizing antibodies at the time of reperfusion. I/R elevated TNF-alpha expression (mRNA and protein), whereas administration of anti-TNF-alpha before reperfusion attenuated TNF-alpha expression. We detected TNF-alpha expression in vascular smooth muscle cells, mast cells, and macrophages, but not in the endothelial cells. I/R induced endothelial dysfunction and superoxide production. Administration of anti-TNF-alpha at the onset of reperfusion partially restored nitric oxide-mediated coronary arteriolar dilation and reduced superoxide production. I/R increased the activity of NAD(P) H oxidase and of xanthine oxidase and enhanced the formation of nitrotyrosine residues in untreated mice compared with shams. Administration of anti-TNF-alpha before reperfusion blocked the increase in activity of these enzymes. Inhibition of xanthine oxidase (allopurinol) or NAD(P) H oxidase (apocynin) improved endothelium-dependent dilation and reduced superoxide production in isolated coronary arterioles following I/R. Interestingly, I/R enhanced superoxide generation and reduced endothelial function in neutropenic animals and in mice treated with a neutrophil NAD(P) H oxidase inhibitor, indicating that the effects of TNF-alpha are not through neutrophil activation. We conclude that myocardial ischemia initiates TNF-alpha expression, which induces vascular oxidative stress, independent of neutrophil activation, and leads to coronary endothelial dysfunction.

Original languageEnglish
Pages (from-to)H2242-H2249
Number of pages8
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume295
Issue number6
DOIs
Publication statusPublished - Dec 2008

Keywords

  • coronary disease
  • endothelium
  • free radicals
  • microcirculation
  • nitric oxide
  • NECROSIS-FACTOR-ALPHA
  • ISCHEMIA/REPERFUSION INJURY
  • HEART-FAILURE
  • CORONARY MICROEMBOLIZATION
  • RHEUMATOID-ARTHRITIS
  • MYOCARDIAL-ISCHEMIA
  • NITRIC-OXIDE
  • LUNG INJURY
  • ETANERCEPT
  • THERAPY

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