Published online before print June 24, 2004, doi: 10.1161/01.RES.0000136519.84279.7a
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Submitted on September 22, 2003
Revised on June 3, 2004
Accepted on June 11, 2004
Ceramide Triggers Weibel-Palade Body Exocytosis
Rinky Bhatia ;
From the Division of Cardiology, Department of Medicine (R.B., K.M., M.Y., C.N.M., W.C., C.J.L.) and the Department of Comparative Medicine (C.N.M.), The Johns Hopkins University School of Medicine, Baltimore, Md.
* To whom correspondence should be addressed. E-mail: clowenst{at}jhmi.edu.
The sphingolipid ceramide mediates a variety of stress responses, including vascular inflammation and thrombosis. Activated endothelial cells release Weibel-Palade bodies, granules containing von Willebrand factor (vWF) and P-selectin, which induce leukocyte rolling and platelet adhesion and aggregation. We hypothesized that ceramide induces vascular inflammation and thrombosis in part by triggering Weibel-Palade body exocytosis. We added ceramide to human aortic endothelial cells and assayed Weibel-Palade body exocytosis by measuring the concentration of vWF released into the media. Exogenous ceramide induces vWF release from endothelial cells in a dose-dependent manner. Activators of endogenous ceramide production, neutral sphingomyelinase, or tumor necrosis factor-
also induce Weibel-Palade body exocytosis. We next studied NO effects on ceramide-induced Weibel-Palade body exocytosis because NO can inhibit vascular inflammation. The NO donor S-nitroso-N-acetylpenicillamine decreases ceramide-induced vWF release in a dose-dependent manner, whereas the NO synthase inhibitor NG-nitro-L-arginine methyl ester increases ceramide-induced vWF release. In summary, our findings show that endogenous ceramide triggers Weibel-Palade body exocytosis, and that endogenous NO inhibits ceramide-induced exocytosis. These data suggest a novel mechanism by which ceramide induces vascular inflammation and thrombosis.
Key words: nitric oxide • sphingomyelin • granule • endothelial cells • N-ethylmaleimide sensitive factor
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