The Effects of Direct Thrombin Inhibition with Dabigatran on Plaque Formation and Endothelial Function in Apolipoprotein E-Deficient Mice

Abstract

The recently developed oral anticoagulant dabigatran (Dabi) etexilate directly inhibits thrombin after activation by plasma esterases to dabigatran. Thrombin is involved in the pathogenesis of atherosclerosis. We investigated the effects of direct thrombin inhibition on atherosclerosis and endothelial function in a hypercholesterolemic mouse model with accelerated atherosclerosis {[apolipoprotein E-deficient (ApoE(Ϫ/Ϫ)] mice}. ApoE(Ϫ/Ϫ) mice were treated with a cholesterol-rich diet for 12 weeks and either dabigatran etexilate (900 mg/kg body weight) or vehicle. Wild-type (C57/B6) mice served as control. Endothelial function was assessed with carbachol (endothelium dependent) by using glyceroltrinitrate (endothelium independent) as control in aortic rings. Atherosclerotic lesion formation was evaluated with Oil Red staining, and vascular collagen content was determined by Sirius Red staining. Reactive oxygen species (ROS) production was determined by semiquantitative immunohistochemical staining. Measurement of dabigatran plasma levels (622.3 Ϯ 169 ng/ml) and a performed coagulation test These data suggest that direct thrombin inhibition in a relevant dosage improved endothelial function and reduced atherosclerotic lesion size, collagen content, and oxidative stress in hypercholesterolemic atherosclerosis. Interference with the coagulation system might provide a therapeutic target to modify atherosclerotic disease progression.

Thrombin Generation and Atherothrombosis: What Does the Evidence Indicate?

“…In the context of atherogenesis and atherosclerosis, TG is linked to early atherosclerosis, likely one of the drivers of this complex process 75. This model is strongly supported by experimental studies 22, 23, 24, 25…”

The Northwick Park Heart Study: evidence from the laboratory

“…Moreover, hypercoagulability is linked to plaque phenotype [51], with effects that support either plaque stability or instability, depending on the plaque stage and the age of the animal, respectively [69,70]. These effects may well be clinically relevant, as three experimental studies have shown that the thrombin inhibitor dabigatran substantially attenuates atherosclerosis in apoE -/-mice [70][71][72]. Although these observations in mouse models are obviously not directly translatable to humans, even minute effects in humans may turn out to be relevant upon prolonged exposure to anticoagulants.…”

Upstream versus downstream thrombin inhibition

“…NOACs are very small molecules that will easily pass the endothelium and interact with coagulation proteases in the vessel wall. Indeed, a number of experimental studies have shown that administration of dabigatran inhibits atherogenesis in mice with an apoE null background, prone to develop atherosclerosis [47][48][49]. These studies also indicated several protective mechanisms resulting from thrombin inhibition, including endothelial cell protection, reduced inflammation by diminished neutrophil influx, and increased plaque stability.…”