Differential Effects of Direct Plasmin Inhibition and Tranexamic Acid on Atherosclerosis Progression and Vascular Remodeling in Apoe/Ldlr Double-Knockout Mice

AIM: The fibrinolytic system may protect against or promote atherosclerosis; however, the effects of distinct antifibrinolytic interventions on plaque development and extracellular matrix (ECM) remodeling remain unclear. METHODS: We compared YO-2, a direct plasmin inhibitor, and tranexamic acid (TXA), a lysine analog that interferes with plasminogen/plasmin binding to fibrin, in Apoe/Ldlr double-knockout mice fed a Western diet. The atherosclerotic burden, plaque structure, vascular marker expression, leukocyte-endothelial interactions, and nitric oxide (NO)-related indices were assessed. RESULTS: YO-2 significantly increased the atherosclerotic lesion area compared to the control, whereas TXA had minimal effects. The thrombolytic activity in the He-Ne laser-induced thrombosis model and NO-related indices did not differ significantly among the groups. Vascular t-PA expression increased in both treatment groups. YO-2 was associated with reduced uPAR and MMP-9 expression and preservation of the internal elastic lamina and medial elastin fibers, suggesting reduced pericellular ECM degradation. TXA increased PAI-1 and TAFI expression without altering uPAR. Both treatments significantly reduced leukocyte rolling, and the E-selectin expression was significantly decreased with YO-2, with a similar trend with TXA. eNOS mRNA expression was significantly higher in both groups, although the corresponding increase in the eNOS protein expression was only a non-significant trend. CONCLUSIONS: Direct plasmin inhibition with YO-2 aggravated atherosclerosis and it was associated with a reduced uPAR/MMP-9 expression and altered vascular ECM remodeling. TXA had limited effects on lesion burden while increasing PAI-1 and TAFI expression. These findings suggest that direct plasmin inhibition and TXA-mediated antifibrinolysis may differentially affect atherosclerosis and vascular remodeling.