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, David J. Lefer, Charles J. Lowenstein

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1247-1254
Number of pages8
JournalCirculation Research
Volume101
Issue number12
DOIs
StatePublished - Dec 2007

Keywords

  • Endothelial
  • Exocytosis
  • Microvascular obstruction
  • Myocardial infarction
  • Vesicle trafficking

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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