The fibrin-derived peptide Bβ15–42 protects the myocardium against ischemia-reperfusion injury

Abstract

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.

The VE‐cadherin binding domain of fibrinogen induces endothelial barrier permeability and enhances transendothelial migration of malignant breast epithelial cells

“…Furthermore, Fg mediates binding of leukocytes to endothelium via heterophilic binding interactions, 30 which may contribute to exudation of plasma Fg into perivascular spaces during neutrophil diapedesis, 31 and FDPs enhance TEM of leukocytes into damaged heart tissue during ischemia-reperfusion injury. 20,22,23 The physiologic balance between fibrin formation and fibrin dissolution is key to the restoration of homeostasis, and much attention has been paid to understanding the mechanisms that regulate this balance. Fibrin deposition occurs in the stroma of a majority of primary tumors, and abundant Fg, but not fibrin, FIGURE 4 -Fg treatment induced gap formation and intracellular relocalization of VE-cadherin in HUVEC.…”

“…14,[26][27][28] Control experiments indicated that Fg added to breast cancer or endothelial cells was not processed further by protease degradation or crosslinking to higher ordered structures (data not shown). Synthetic peptides corresponding to the Fg b-chain primary structure were custom synthesized as previously described, 11 and include b , b [15][16][17][18][19][20][21][22][23][24][25][26][27] , b 18-31 and b [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] (Table I). Fibrinopeptide A (Bachem) was used as a nonspecific peptide for permeability studies.…”

“…The negative control peptide corresponding to fibrinopeptide A induced minimal %FITC-Dextran Flux compared with Fg or peptide b 15-42 (#p < 0.0001); however, the 13% relative fluorescence was significant (-p 5 0.001) compared with basal levels that were 1% of intact Fg-induced permeability. Peptides missing b 15-17 residues (b [18][19][20][21][22][23][24][25][26][27][28][29][30][31] or b [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] ) or truncated at the C-terminus (b [15][16][17][18][19][20][21][22][23][24][25][26][27] (Fig. 2c).…”

“…19 Furthermore, peptide b 15-42 competes with FDPs for binding to VE-cadherin, thereby preventing Fg-induced transendothelial migration (TEM) of leukocytes in acute or chronic models of myocardial ischemia-reperfusion injury. [20][21][22][23] A number of challenges confront metastatic tumor cells, including TEM, safe passage in circulation and stabilization of tumor emboli at distant sites to support growth and tumor angiogenesis. It is unknown whether fibrin(ogen) plays a role in TEM of cancer cells-critical steps in both intravasation to disseminate tumor cells and extravasation to establish metastatic growth.…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…In a mouse model of reperfused myocardial infarction, fibrin-mediated interactions contributed to early injury by accentuating the inflammatory response (54). Treatment with a naturally occurring peptide that competes with the fibrin fragment N-terminal disulfide knot-II (an analog of the fibrin E1 fragment) for binding to vascular endothelial cadherin reduced infarct size, attenuating leukocyte infiltration in the ischemic myocardium in both rodent and large animal models (54,55). Unfortunately, the effects of the peptide in a small clinical trial were much less impressive.…”