Journal
CIRCULATION RESEARCH
Volume 101, Issue 12, Pages 1247-1254Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.107.162610
Keywords
exocytosis; vesicle trafficking; microvascular obstruction; endothelial; myocardial infarction
Funding
- NHLBI NIH HHS [R01 HL63706, P01 HL65608, P01 HL056091, P01 HL065608, 2R01 HL-060849-08, R01 HL074061, R01 HL063706, 5P01HL056091, P01 HL56091] Funding Source: Medline
- NIAID NIH HHS [5R01AI042387-1, R01 AI042387] Funding Source: Medline
- NIDDK NIH HHS [F32DK077380-01, F32 DK077380] Funding Source: Medline
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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.
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