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Endostatin uncouples NO and Ca²⁺ response to bradykinin through enhanced O₂^–· production in the intact coronary endothelium

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 3 March 2004 ; accepted in final form 1 October 2004

The present study tested the hypothesis that endostatin stimulates superoxide (O₂^–·) production through a 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 coronary endothelial cells. With the use of 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 conditions, 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 h, this BK-induced NO production was reduced by 89%, whereas [Ca²⁺]_i was unchanged. With the conversion rate of L-[³H]arginine to L-[³H]citrulline measured, 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 contribute importantly to endostatin-induced endothelial dysfunction.

collagen; sphingolipid; free radicals; signal transduction; coronary artery

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