Differential Effects of Direct Plasmin Inhibition and Tranexamic Acid on Atherosclerosis Progression and Vascular Remodeling in Apoe/Ldlr Double-Knockout Mice
Abstract
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.
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BibTeX
@article{yoshihama2026differential,
title = {{Differential Effects of Direct Plasmin Inhibition and Tranexamic Acid on Atherosclerosis Progression and Vascular Remodeling in Apoe/Ldlr Double-Knockout Mice}},
author = {Natsumi Yoshihama and Nana Kurisu and Kentaro Shimatani and Kanae Hyodo and Naotaka Ohta and Hiromitsu Ishii and Tsutomu Yamashita},
journal = {Journal of Atherosclerosis and Thrombosis},
year = {2026},
month = oct,
doi = {10.5551/jat.66328},
url = {https://www.jstage.jst.go.jp/article/jat/advpub/0/advpub_66328/_article},
note = {CC BY-NC-SA},
}
RIS
TY - JOUR
TI - Differential Effects of Direct Plasmin Inhibition and Tranexamic Acid on Atherosclerosis Progression and Vascular Remodeling in Apoe/Ldlr Double-Knockout Mice
AU - Natsumi Yoshihama
AU - Nana Kurisu
AU - Kentaro Shimatani
AU - Kanae Hyodo
AU - Naotaka Ohta
AU - Hiromitsu Ishii
AU - Tsutomu Yamashita
PY - 2026
DA - 2026/10/15
JO - Journal of Atherosclerosis and Thrombosis
DO - 10.5551/jat.66328
UR - https://www.jstage.jst.go.jp/article/jat/advpub/0/advpub_66328/_article
AB - 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.
SN - 1880-3873
SN - 1340-3478
ER -