The fibrin-derived peptide Bbeta15-42 protects the myocardium against ischemia-reperfusion injury.
In the event of a myocardial infarction, current interventions aim to reopen the occluded vessel to reduce myocardial damage and injury. Although reperfusion is essential for tissue salvage, it can cause further damage and the onset of inflammation. We show a novel anti-inflammatory effect of a fibrin-derived peptide, Bbeta15-42. This peptide competes with the fibrin fragment N-terminal disulfide knot-II (an analog of the fibrin E1 fragment) for binding to vascular endothelial (VE)-cadherin, thereby preventing transmigration of leukocytes across endothelial cell monolayers. In acute or chronic rat models of myocardial ischemia-reperfusion injury, Bbeta15-42 substantially reduces leukocyte infiltration, infarct size and subsequent scar formation. The pathogenic role of fibrinogen products is further confirmed in fibrinogen knockout mice, in which infarct size was substantially smaller than in wild-type animals. Our findings conclude that the interplay of fibrin fragments, leukocytes and VE-cadherin contribute to the pathogenesis of myocardial damage and reperfusion injury. The naturally occurring peptide Bbeta15-42 represents a potential candidate for reperfusion therapy in humans.
Petzelbauer
Peter
P
Department of General Dermatology, Medical University of Vienna, 18-20 Waehringer Guertel, Vienna, 1090, Austria.
Zacharowski
Paula A
PA
Miyazaki
Yasuhiro
Y
Friedl
Peter
P
Wickenhauser
Georg
G
Castellino
Francis J
FJ
Gröger
Marion
M
Wolff
Klaus
K
Zacharowski
Kai
K
D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D005338:Fibrin Fibrinogen Degradation Products; D010446:Peptide Fragments; D000099152:Cadherin 5; C500232:NDSK-II; C033786:fibrinogen Bbeta (15-42)