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(Circulation Research. 2004;95:319.)
© 2004 American Heart Association, Inc.

Cellular Biology

Ceramide Triggers Weibel–Palade Body Exocytosis

Rinky Bhatia^*, Kenji Matsushita^*, Munekazu Yamakuchi, Craig N. Morrell, Wangsen Cao, Charles J. Lowenstein

From the Division of Cardiology, Department of Medicine (R.B., K.M., M.Y., C.N.M., W.C., C.J.L.) and the Departments of Comparative Medicine and Pathology (C.N.M.), The Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Charles J. Lowenstein, 950 Ross Bldg, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Baltimore, MD 21205. 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 N^G-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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