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

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Publisher: American Physiological Society
Document Type: Author abstract; Clinical report
Length: 232 words

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Abstract :

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. coronary disease; endothelium; free radicals; microcirculation; nitric oxide

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Gale Document Number: GALE|A191766269