Factor XI Deficiency Protects Against Atherogenesis in Apolipoprotein E/Factor XI Double Knockout Mice

Abstract

Objective Atherosclerosis and atherothrombosis are still major causes of mortality in the Western world, even after the widespread use of cholesterol-lowering medications. Recently, an association between local thrombin generation and atherosclerotic burden has been reported. Here, we studied the role of factor XI (FXI) deficiency in the process of atherosclerosis in mice. Approach and Results Apolipoprotein E/FXI double knockout mice, created for the first time in our laboratory. There was no difference in cholesterol levels or lipoprotein profiles between apolipoprotein E knockout and double knockout mice. Nevertheless, in 24-week-old double knockout mice, the atherosclerotic lesion area in the aortic sinus was reduced by 32% (P=0.004) in comparison with apolipoprotein E knockout mice. In 42-week-old double knockout mice, FXI deficiency inhibited atherosclerosis progression significantly in the aortic sinus (25% reduction, P=0.024) and in the aortic arch (49% reduction, P=0.028), with a prominent reduction of macrophage infiltration in the atherosclerotic lesions. Conclusions FXI deprivation was shown to slow down atherogenesis in mice. The results suggest that the development of atherosclerosis can be prevented by targeting FXI.

Factor XI deficiency is not associated with an increased risk of pneumonia and pneumonia‐related mortality

“…The idea to search for the relationship between FXI deficiency and pneumonia came from the following observations: (i) a reduced influx of leucocytes to the site of infections and inflammation has been reported in diverse mice models involving FXI KO mice in comparison with wild‐type mice . (ii) A prominent reduction in macrophage infiltration has been found in the atherosclerotic lesions in apo E/FXI KO mice in comparison with apoE KO mice . (iii) Human neutrophils have a reduced capacity to phagocytose bacteria when the activation of FXI is inhibited .…”

Fibrinogen and Fibrin in Hemostasis and Thrombosis

“…Mice with deficiency in apolipoprotein E ( Apoe −/− ) spontaneously develop atherosclerotic lesions, but Apoe −/− mice with genetic FXI deficiency show reduced atherosclerosis progression. 56 Moreover, anti-FXI ASO treatment reduces thrombus formation and fibrin deposition in a model of plaque rupture in Apoe −/− mice. 57 Thus, FXI inhibition may also be effective for reducing arterial thrombosis in humans.…”

Factor XI as a Therapeutic Target

“…While reduced fibrin deposition may have a role in the tissue sparing effect, alteration of the inflammatory response could be involved. Shnerb-Ganor et al reported that fXI deficiency reduces atherosclerotic plaque growth and plaque infiltration by macrophages in ApoE deficient mice [35]. van Montfoort et al also noted reduced macrophage infiltration and an absence of neutrophils in arteries in ApoE-null mice after knockdown of fXI expression [36].…”