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Articles in PresS, published online ahead of print November 7, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00697.2002
Submitted on August 9, 2002
Accepted on October 30, 2002
1 Department of Pharmacolgoy, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Toxicology and Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: pli{at}mcw.edu.
We tested the hypothesis that ceramide induces endothelial dysfunction in small coronary arteries via NADPH oxidase-mediated superoxide and resulting peroxynitrite formation. Using dihydroethidium as a superoxide indicator, C2-ceramide was found to increase superoxide concentrations in the endothelium of small coronary arteries. This increase was inhibited by NADPH oxidase inhibitors N-vanillylnonanamide, apocynin and diphenylene iodonium. NADPH oxidase expression was confirmed in endothelial cells, as indicated by the immunoblotting of its subunits gp91phox and p47phox. C2-ceramide increased NADPH oxidase activity by 52%, which was blocked by NADPH oxidase inhibitors but not by inhibitors of NO synthase, xanthine oxidase and mitochondrial electron transport chain enzymes. By Western blot analysis, ceramide-induced NADPH oxidase activation was found to be associated with the translocation of p47phox to the membrane. In isolated and pressurized small coronary arteries, N-vanillylnonanamide, apocynin, or uric acid, a peroxynitrite scavenger, largely restored the inhibitory effects of ceramide on bradykinin- and A23187-induced vasorelaxation. Using nitrotyrosine as a marker, C2-ceramide was found to increase peroxynitrite in small coronary arteries, which could be blocked by uric acid. We conclude that NADPH oxidase-mediated superoxide production and subsequent peroxynitrite formation mediate ceramide-induced endothelial dysfunction in small coronary arteries.
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