Changes in spontaneous thrombolytic activity during progression of atherosclerosis in Apo and LDLR double knockout mice.

Background: Atherosclerosis is characterized by a hypercoagulable state, during which both coagulation and thrombolytic factors are activated simultaneously. However, details regarding the thrombolytic pathway in this context remain unknown. Here we investigated the changes in spontaneous thrombolytic activity during atherosclerotic progression in ApoLDLR double-knockout mice (DKO group).

Methods: We fed DKO mice and their controls (C57Bl6 mice) a high-fat diet for a total of 22 weeks and evaluated them at 14 and 22 weeks. The amount of atherosclerosis was estimated as the ratio of the atherosclerotic to total aortic intimal area. In addition, we used immunohistochemistry to analyze the expression of PAI-1, t-PA, and 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 increased and thrombolytic activity was decreased in DKO group compared with the control group. Furthermore, the plasma PAI-1 level was 3 times greater in the DKO group than in the control group. In support of these results, immunohistochemistry showed increased PAI-1 expression in the DKO group, whereas t-PA and eNOS expression was greater in the control group.

Conclusion: Progression of atherosclerosis led to a reduction in thrombolytic activity through decreases in t-PA and eNOS levels and an increase in PAI-1 production. These findings indicate that decreases in factors that promote spontaneous thrombolytic activity may indicate increased risk for the progression of atherosclerosis.