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CARDIOVASCULAR

A Novel Inhibitor of N-Ethylmaleimide-Sensitive Factor Decreases Leukocyte Trafficking and Peritonitis

Departments of Comparative Medicine (C.N.M.), Pathology (C.N.M., C.J.L.), and Medicine (K.M., C.J.L.), The Johns Hopkins University School of Medicine, Baltimore, Maryland

Endothelial exocytosis is an early stage in the process of leukocyte trafficking. N-ethylmaleimide-sensitive factor (NSF) plays a critical role in regulating exocytosis. We hypothesized that inhibitors of NSF decrease endothelial exocytosis and vascular inflammation. We designed a novel fusion polypeptide consisting of a human immunodeficiency virus transactivator of transcription (TAT) protein transduction domain joined to a NSF homohexamerization domain. We show that this TAT-NSF polypeptide inhibits the ATPase activity and the disassembly activity of NSF. Furthermore, the TAT-NSF polypeptide decreases endothelial cell exocytosis and reduces leukocyte adherence to endothelial cells in culture. Finally, the TAT-NSF polypeptide inhibits leukocyte rolling on murine venules in vivo and inhibits leukocyte trafficking into the peritoneal cavity in a murine model of experimental peritonitis. These data suggest that NSF is a critical regulator of leukocyte trafficking in vivo. Novel compounds that inhibit the exocytic machinery in endothelial cells may be useful anti-inflammatory drugs.

Address correspondence to: Charles J. Lowenstein, 950 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205. E-mail: clowenst{at}jhmi.edu

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