Fibrin(ogen) and its fragments in the pathophysiology and treatment of myocardial infarction

Abstract

The occlusion of a coronary artery leads to ischemia of the myocardium, while permanent occlusion results in cell death and myocardial dysfunction. Early restoration of blood flow is the only means to reduce or prevent myocardial necrosis, but-paradoxically-reperfusion itself contributes to injury of the heart. In animal models, this phenomenon is well described, and there are many different unrelated approaches to reduce reperfusion injury. In humans, however, pharmacological interventions have so far failed to reduce myocardial reperfusion injury. We summarize the pathogenesis of reperfusion injury, detailing the role of fibrin(ogen) and its derivatives. Moreover, we introduce a new concept for fibrin derivatives as potential targets for reperfusion therapy.

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

“…Both MoAbs T2G1 (anti-FgBb [15][16][17][18][19][20][21] ) and BV9 (anti-VE-cadherin EC3-EC4), but not MoAb 18C6 (anti-FPB Bb [1][2][3][4][5][6][7][8][9][10][11][12][13][14], partially inhibited Fg-induced FITCDextran Flux, implicating VE-cadherin and Fg-b in mechanisms of Fg-induced EC permeability. Fg is capable of inducing permeability of different types of barrier EC, as Fg also induced permeability of a microvascular EC barrier, whereas it did not induce permeability of an epithelial cell barrier.…”

“…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.…”

Bβ15–42 Attenuates the Effect of Ischemia-Reperfusion Injury in Renal Transplantation

“…11,12 If bound to VEcadherin, fibrin fragments have open binding sites that can interact with leukocytes, which leads to endothelial attachment and transmigration. 13 B␤ is a breakdown product of fibrin that corresponds to the VE-cadherin binding sequence of the fibrin ␤-chain but which lacks the leukocyte binding site. 13 As a consequence, B␤ binding to VE-cadherin can competitively inhibit endothelial leukocyte adhesion.…”