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(Circulation Research. 2007;101:1247.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Inhibition of N-Ethylmaleimide–Sensitive Factor Protects Against Myocardial Ischemia/Reperfusion Injury

John W. Calvert, Susheel Gundewar, Munekazu Yamakuchi, Pierce C. Park, William M. Baldwin, III, David J. Lefer, Charles J. Lowenstein

From the Department of Medicine (J.W.C., S.G., D.J.L.), Division of Cardiology and Department of Pathology, Albert Einstein College of Medicine, Bronx, NY; and Departments of Medicine (M.Y., P.C.P., C.J.L.) and Pathology (W.M.B., C.J.L.), The Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Charles J. Lowenstein, MD, Departments of Medicine and Pathology, The Johns Hopkins University School of Medicine, 950 Ross Building, 720 Rutland Ave, Baltimore, MD 21205. E-mail clowenst{at}jhmi.edu

Exocytosis of endothelial granules promotes thrombosis and inflammation and may contribute to the pathophysiology of early reperfusion injury following myocardial ischemia. TAT-NSF700 is a novel peptide that reduces endothelial exocytosis by inhibiting the ATPase activity and disassembly activity of N-ethylmaleimide–sensitive factor (NSF), a critical component of the exocytic machinery. We hypothesized that TAT-NSF700 would limit myocardial injury in an in vivo murine model of myocardial ischemia/reperfusion injury. Mice were subjected to 30 minutes of ischemia followed by 24 hours of reperfusion. TAT-NSF700 or the scrambled control peptide TAT-NSF700scr was administered intravenously 20 minutes before the onset of ischemia. Myocardial ischemia/reperfusion caused endothelial exocytosis, myocardial infarction, and left ventricular dysfunction. However, TAT-NSF700 decreased von Willebrand factor levels after myocardial ischemia/reperfusion, attenuated myocardial infarct size by 47%, and preserved left ventricular structure and function. These data suggest that drugs targeting endothelial exocytosis may be useful in the treatment of myocardial injury following ischemia/reperfusion.

Key Words: exocytosis • vesicle trafficking • microvascular obstruction • endothelial • myocardial infarction