The Effects of the Fibrin-Derived Peptide B??15-42 in Acute and Chronic Rodent Models of Myocardial Ischemia-Reperfusion

Abstract

Many compounds have been shown to prevent reperfusion injury in various animal models, although to date, translation into clinic has revealed several obstacles. Therefore, the National Heart, Lung, and Blood Institute convened a working group to discuss reasons for such failure. As a result, the concept of adequately powered, blinded, randomized studies for preclinical development of a compound has been urged. We investigated the effects of a fibrin-derived peptide Bbeta(15-42) in acute and chronic rodent models of ischemia-reperfusion at three different study centers (Universities of Dusseldorf and Vienna, TNO Biomedical Research). A total of 187 animals were used, and the peptide was compared with the free radical scavenger Tempol, CD18 antibody, alpha-C5 antibody, and the golden standard, ischemic preconditioning. We show that Bbeta(15-42) robustly and reproducibly reduced infarct size in all models of ischemia-reperfusion. Moreover, the peptide significantly reduced plasma levels of the cytokines interleukin 1beta, tumor necrosis factor alpha, and interleukin 6. In rodents, Bbeta(15-42) inhibits proinflammatory cytokine release and is cardioprotective during ischemia-reperfusion injury.

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.…”

“…47 Not only does peptide b 15-42 significantly reduce recruitment of inflammatory cells to regions of ischemic-reperfusion injury, it also reduces plasma levels of IL-1b, TNF-a and IL-6. 23 Peptide b 15-42 is a natural FDP; it is one of the first regions of the insoluble clot to be released into circulation during plasmin-mediated fibrinolysis. Inhibition of IL-6 production by b 15-42 would lead to feedback inhibition of elevated production of plasma Fg induced by IL-6 in response to systemic inflammation.…”

“…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).…”

“…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.…”

“…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.…”