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ARTICLESThe fibrin-derived peptide B1542 protects the
myocardium against ischemia-reperfusion injury.com/naturemedicinehttp://www.nature2005 Nature Publishing Group Peter Petzelbauer1,2, Paula A Zacharowski3, Yasuhiro Miyazaki1, Peter Friedl1, Georg Wickenhauser1,
Francis J Castellino4, Marion Grger2, Klaus Wolff1,2 & Kai Zacharowski3In 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, B1542. 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, B1542 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 B1542 represents a
potential candidate for reperfusion therapy in humans.It is a major therapeutic goal of modern cardiology to invent approaches
aimed at minimizing myocardial necrosis and improving cardiac repair
after myocardial infarction. Surgical and pharmaceutical procedures
aim to reperfuse the infarcted area, but the sudden reinitiation of blood
flow causes local inflammation leading to irreversible endothelial and
myocardial damage, thereby reducing the benefit of reperfusion1,2.Inflammation requires the migration of circulating leukocytes
from the bloodstream into tissue. This is coordinated by a multistep process consisting of tethering, rolling, activation and adhesion
of leukocytes to endothelial surfaces. To accomplish the final step
(transmigration), leukocytes must cross the multilayered molecular
zipper of interendothelial junctions. Molecules configuring this zipper
include junctional adhesion molecules (JAM), platelet endothelial cell
adhesion molecule 1 (PECAM-1, CD31), CD99 and VE-cadherin
(CD144). Each of these molecules participates in zipper formation by
homophilic adhesion with neighboring endothelial cells. PECAM-1 and
CD99 contribute to leukocyte transmigration by providing homophilic
and/or heterotypic adhesion to leukocytes35. So far receptor-ligand
interactions of VE-cadherin to leukocytes have not been shown.Currently it is thought that leukocytes do not open or disrupt
VE-cadherin junctions, but simply move...