Role of ceramide in TNF-α-induced impairment of endothelium-dependent vasorelaxation in coronary arteries
- 1 November 2002
- journal article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 283 (5), H1785-H1794
- https://doi.org/10.1152/ajpheart.00318.2002
Abstract
The present study tested the hypothesis that ceramide, a sphingomylinase metabolite, serves as an second messenger for tumor necrosis factor-α (TNF-α) to stimulate superoxide production, thereby decreasing endothelium-dependent vasorelaxation in coronary arteries. In isolated bovine small coronary arteries, TNF-α (1 ng/ml) markedly attenuated vasodilator responses to bradykinin and A-23187. In the presence of NG-nitro-l-arginine methyl ester, TNF-α produced no further inhibition on the vasorelaxation induced by these vasodilators. With the use of 4,5-diaminofluorescein diacetate fluorescence imaging analysis, bradykinin was found to increase nitric oxide (NO) concentrations in the endothelium of isolated bovine small coronary arteries, which was inhibited by TNF-α. Pretreatment of the arteries with desipramine (10 μM), an inhibitor of acidic sphingomyelinase, tiron (1 mM), a superoxide scavenger, and polyethylene glycol-superoxide dismutase (100 U/ml) largely restored the inhibitory effect of TNF-α on bradykinin- and A-23187-induced vasorelaxation. In addition, TNF-α activated acidic sphingomyelinase and increased ceramide levels in coronary endothelial cells. We conclude that TNF-α inhibits NO-mediated endothelium-dependent vasorelaxation in small coronary arteries via sphingomyelinase activation and consequent superoxide production in endothelial cells.Keywords
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