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

Authors

Natsumi Yoshihama, Nana Kurisu, Kentaro Shimatani, Kanae Hyodo, Naotaka Ohta, Hiromitsu Ishii, Tsutomu Yamashita

Published in

Journal of atherosclerosis and thrombosis. Oct 15, 2026. Epub Oct 15, 2026.

Abstract

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.
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.
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.
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.

PMID:
42875231
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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