The beneficial effects of a direct thrombin inhibitor, dabigatran etexilate, on the development and stability of atherosclerotic lesions in apolipoprotein e-deficient mice

摘要

Purpose Dabigatran etexilate (DE) constitutes a novel, direct thrombin inhibitor. Regarding the association of thrombin with atherogenesis, we assessed the effects of DE on the development and stability of atherosclerotic lesions in apolipoprotein-E deficient (ApoE-/-) mice. Materials-methods Fifty male ApoE-/- mice were randomized to receive western-type diet either supplemented with DE 7.5 mg DE/g chow) (DE-group, n025) or matching placebo as control (CO-group, n025) for 12 weeks. After this period, all mice underwent carotid artery injury with ferric chloride and the time to thrombotic total occlusion (TTO) was measured. Then, mice were euthanatized and each aortic arch was analyzed for the mean plaque area, the content of macrophages, elastin, collagen, nuclear factor kappaB (NF?B), vascular cell adhesion molecule-1 (VCAM-1), matrix metalloproteinase-9 (MMP-9) and its inhibitor (TIMP-1). Results DE-group showed significantly longer TTO compared to CO-group (8.9±2.3 min vs 3.5±1.1 min, p0.001) and the mean plaque area was smaller in DE-group than CO-group (441.00±160.01×103μm2 vs 132.12±32.17× 10 3μm 2, p0.001). Atherosclerotic lesions derived from DE-treated mice showed increased collagen (p00.043) and elastin (p00.031) content, thicker fibrous caps (p0.001) and reduced number of internal elastic lamina ruptures per mm of arterial girth (p0.001) when compared to COgroup. Notably, DE treatment seemed to promote plaque stability possibly by reducing concentrations of NF?B, VCAM-1, macrophages and MMP-9 and increasing TIMP-1 within atherosclerotic lesions (p0.05). Conclusions DE attenuates arterial thrombosis, reduces lesion size and may promote plaque stability in ApoE-/- mice. The plaque-stabilizing effects of chronic thrombin inhibition might be the result of the favorable modification of inflammatory mechanisms.