Fibrin-derived Peptide Bβ15-42 and Earthworm Fibrinolytic Enzyme A Inhibit Atherosclerosis and Inflammation via the VE-cadherin Pathway

Abstract Elevated fibrinogen increases risk for cardiovascular and cerebrovascular diseases. The biological effects of the fibrin-derived peptide Bβ15–42 are different from fibrin and promote vascular and anti-inflammatory effects. Fragments of fibrinogen cleavage by earthworm fibrinolytic enzyme A (EFEa) are structurally similar to Bβ15–42. Therefore, we evaluated if Bβ15–42 and EFEa have anti-atherosclerotic effects. To investigate the anti-atherosclerotic effect of Bβ15–42 and EFEa, we used New Zealand rabbits fed a high cholesterol diet to promote atherosclerosis. Human umbilical vascular endothelial cells with high expression of VE-cadherin were used to determine the mechanism of action of Bβ15–42 and EFEa to inhibit the deleterious effect of fibrin. Both Bβ15–42 and EFEa significantly reduced atherosclerosis in rabbits fed a high cholesterol diet. Vascular fibrinogen deposition and inflammatory cell aggregation was significantly reduced in rabbits treated with Bβ15–42 or EFEa. In addition, Bβ15–42 and EFEa stabilized the structure of endothelial cells and decreased inflammatory cell migration. Bβ15–42 and EFEa protected endothelial cell function by reducing the effect of fibrinogen in the VE-cadherin pathway. Therefore, the fibrin-derived Bβ15–42 peptide exhibited anti-atherosclerotic effects and reduced vascular fibrinogen deposition and inflammatory cell aggregation in the aorta. Furthermore, EFEa has similar Bβ15-42-like anti-atherosclerotic effects.