Interaction of fibrin with VE-cadherin and anti-inflammatory effect of fibrin-derived fragments.

Interaction of fibrin with VE-cadherin and anti-inflammatory effect of fibrin-derived fragments.
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DOI:
10.1111/j.1538-7836.2011.04438.x
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发表时间:
2011-09
期刊:
Journal of thrombosis and haemostasis : JTH
影响因子:
--
通讯作者:
Medved L
Medved L
中科院分区:
其他
文献类型:
--
作者:
Yakovlev S;Gao Y;Cao C;Chen L;Strickland DK;Zhang L;Medved L

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The interaction of fibrin βN-domain with VE-cadherin on endothelial cells was implicated in transendothelial migration of leukocytes and theβ15-42 fragment representing part of this domain was shown to inhibit this process. However, our previous study revealed that only a dimeric (β15-66)2 fragment corresponding to the full-length βN-domain and mimicking its dimeric arrangement in fibrin bound to VE-cadherin. To test our hypothesis that dimerization of β15-42-containing fragments increases their affinity to VE-cadherin and ability to inhibit transendothelial migration of leukocytes. Interaction of β15-42-containing fragments with VE-cadherin was characterized by ELISA and surface plasmon resonance. Inhibitory effect of such fragments was tested in vitro using leukocyte transendothelial migration assay and in vivo using mouse models of peritonitis and myocardial ischemia-reperfusion injury. First, we prepared the monomeric β15-42 and β15-64 fragments and their dimeric forms, (β15-44)2 and (β15-66)2, and studied their interaction with fibrin-binding domain of VE-cadherin, VE-cad(3). The experiments revealed that both dimeric fragments bound to VE-cad(3) with high affinity while the affinities of monomeric β15-42 and β15-64 were significantly lower. Next, we tested the ability of these fragments to inhibit leukocyte transmigration in vitro and infiltration into the inflamed peritoneum in vivo and found that the inhibitory effects of the dimers on these processes were also superior. Furthermore, dimeric (β15-44)2 significantly reduced myocardial injury induced by ischemia-reperfusion. The results confirm our hypotheses and indicate that dimeric (β15-66)2 and (β15-44)2, which exhibited much higher affinity to VE-cadherin, are highly effective in suppressing inflammation by inhibiting leukocyte transmigration.
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