Effects of Long-term Thrombin Inhibition (Dabigatran Etexilate) on Spontaneous Thrombolytic Activity during the Progression of Atherosclerosis in ApoE−/−–LDLR−/− Double-Knockout Mice

Tomohide Sanda; Manami Yoshimura; Kanae Hyodo; Hiromitu Ishii; Tsutomu Yamashita

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자료유형: 학술저널

저자정보: Tomohide Sanda (Kobe Gakuin University) Manami Yoshimura (Kobe Gakuin University) Kanae Hyodo (Kobe Gakuin University) Hiromitu Ishii (Kobe Gakuin University) Tsutomu Yamashita (Kobe Gakuin University)

저널정보: 대한심장학회 Korean Circulation Journal Korean Circulation Journal Vol.50 No.9

발행연도: 2020.1

수록면: 804 - 816 (13page)

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Background and Objectives: Atherosclerosis is characterized by a hypercoagulable state, during which coagulation and fibrinolytic factors are activated simultaneously. However, details regarding the thrombolytic pathway in this context remain unknown. Here we investigated how direct long-term inhibition of thrombin influenced spontaneous thrombolytic activity during atherosclerotic progression in apolipoprotein E (ApoE)–/––low density lipoprotein receptor (LDLR)–/– double-knockout mice. Methods: All mice received either standard chow (placebo group) or dabigatran-containing chow for 22 weeks, after which we evaluated them. The amount of atherosclerosis was estimated as the ratio of the atherosclerotic area to the total aortic intimal area. In addition, we used immunohistochemistry to analyze the expression of tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), and endothelial nitric oxide synthase (eNOS) in atherosclerotic regions. To evaluate thrombolysis, we used a He–Ne laser to induce thrombosis in vessels of the cremaster muscle and then measured the thrombus volume over time. Results: The atherosclerotic area was smaller and thrombolytic activity greater in the dabigatran-treated group than in the placebo group. Furthermore, according to the thrombolysis model, spontaneous thrombolytic activity was increased in the dabigatran-treated mice compared with the placebo mice. In support of these results, immunohistochemistry demonstrated decreased expression of PAI-1 and TAFI but increased expression of eNOS in the dabigatran group compared with the placebo group. However, t-PA expression did not differ between groups. Conclusions: Direct long-term inhibition by dabigatran etexilate of thrombin led to an increase in spontaneous thrombolytic activity decreasing the expression of PAI-1 and TAFI.

#Anticoagulants #Atherosclerosis #Fibrinolysis #PAI-1 #TAFI #Dabigatran etexilate

참고문헌 (30)

참고문헌 신청

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