Inhibition of N-ethylmaleimide-sensitive factor protects against myocardial ischemia/reperfusion injury.

Abstract

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.

• Authors: John W Calvert, Susheel Gundewar, Munekazu Yamakuchi, Pierce C Park, William M Baldwin 3rd, David J Lefer, Charles J Lowenstein
• Journal: Circulation research (Circ Res) Vol. 101 Issue 12 Pg. 1247-54 (Dec 07 2007) ISSN: 1524-4571 [Electronic] United States
• PMID: 17932325 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Peptides
• N-Ethylmaleimide-Sensitive Proteins

Topics

• Animals
• Exocytosis (drug effects, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardial Ischemia (drug therapy, enzymology, pathology)
• Myocardial Reperfusion Injury (enzymology, pathology, prevention & control)
• N-Ethylmaleimide-Sensitive Proteins (antagonists & inhibitors, physiology)
• Peptides (physiology, therapeutic use)
• Ventricular Function, Left (drug effects, physiology)