Inhibition of N-ethylmaleimide-sensitive factor protects against myocardial ischemia/reperfusion injury.
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.
Calvert
John W
JW
Department of Medicine, Division of Cardiology and Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
Gundewar
Susheel
S
Yamakuchi
Munekazu
M
Park
Pierce C
PC
Baldwin
William M
WM
Lefer
David J
DJ
Lowenstein
Charles J
CJ
D000818:Animals; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D010455:Peptides / Q000502:physiology / Q000627:therapeutic use; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D010455:Peptides; D052066:N-Ethylmaleimide-Sensitive Proteins