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

• Published in: Circulation research Vol. 101; no. 12; pp. 1247 - 1254
• Main Authors: Calvert, John W, Gundewar, Susheel, Yamakuchi, Munekazu, Park, Pierce C, Baldwin, William M, Lefer, David J, Lowenstein, Charles J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 07.12.2007; Lippincott
• Subjects: Animals; Biological and medical sciences; Cardiology. Vascular system; Coronary heart disease; Exocytosis - drug effects; Exocytosis - physiology; Fundamental and applied biological sciences. Psychology; Heart; Male; Medical sciences; Mice; Mice, Inbred C57BL; Myocardial Ischemia - drug therapy; Myocardial Ischemia - enzymology; Myocardial Ischemia - pathology; Myocardial Reperfusion Injury - enzymology; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Myocarditis. Cardiomyopathies; N-Ethylmaleimide-Sensitive Proteins - antagonists & inhibitors; N-Ethylmaleimide-Sensitive Proteins - physiology; Peptides - physiology; Peptides - therapeutic use; Ventricular Function, Left - drug effects; Ventricular Function, Left - physiology; Vertebrates: cardiovascular system; Myocardial infarction; Vesicle; Ischemia reperfusion; Cardiovascular disease; Myocardial ischemia; Exocytosis; Coronary heart disease; Myocardial disease; Endothelium; Vascular disease; Microcirculation; Vertebrata; Mammalia; endothelial; Circulatory system; Inhibition; microvascular obstruction; vesicle trafficking
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.107.162610

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.