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1 Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: pli{at}mcw.edu.
The present study tested the hypothesis that endostatin stimulates superoxide (O2.-) production through ceramide-mediating signaling pathway and thereby results in an uncoupling of bradykinin (BK)-induced increases in intracellular Ca2+ concentration ([Ca2+]i) from nitric oxide (NO) production in endothelial cells. Using high-speed wavelength switching fluorescence imaging techniques, the [Ca2+]i and NO levels were simultaneously monitored in the intact endothelium of freshly-isolated bovine coronary arteries. Under control condition, BK was found to increase NO production and [Ca2+]i in parallel. When the arteries were pretreated with 100 nM human recombinant endostatin for 1 hr, however, this BK-induced NO production was reduced by 89%, while [Ca2+]i unchanged. By measuring the conversion rate of 3H-L-arginine to 3H-L-citruline, endostatin had no effect on endothelial NO synthase (NOS) activity, but it stimulated ceramide by activation of sphingomyelinase (SMase)whereby O2.- production was enhanced in endothelial cells. O2.- scavenging by tiron and inhibition of NAD(P)H oxidase by apocynin markedly reversed the effect of endostatin on the NO response to BK. These results indicate that endostatin increases intracellular ceramide levels, which enhances O2.- production through activation of NAD(P)H oxidase. This ceramide-O2.- signaling pathway may importantly contribute to endostatin-induced endothelial dysfunction.
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