Targeting Coagulation Factor Xa Promotes Regression of Advanced Atherosclerosis in Apolipoprotein-E Deficient Mice
Authors: Stefan Heitmeier
Rick H van Gorp
Hugo Ten Cate
Jens J N Posma
Nigel Mackman
Rene van Oerle
Armand M G Jaminon
Jelle J Posthuma
Leon J Schurgers
Henri M H Spronk
Peter Leenders
Journal: Scientific Reports (2019)
Discipline: Multidisciplinary
Keywords: Atherosclerosis; Plaque rupture; Atherothrombosis; Factor Xa; Protease activated receptors
Affiliations: Laboratory for Clinical Thrombosis and Haemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands., Department of Surgery, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands., Department of Pharmacology-Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands., Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands., Thrombosis and Hemostasis Program, Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Research & Development,Pharmaceuticals, Bayer AG, Wuppertal, Germany., Laboratory for Clinical Thrombosis and Haemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands. .

Abstract:  Atherosclerosis is a progressive inflammatory vascular disorder, complicated by plaque rupture and subsequently atherothrombosis. In vitro studies indicate that key clotting proteases, such as factor Xa (FXa), can promote atherosclerosis, presumably mediated through protease activated receptors (PARs). Although experimental studies showed reduced onset of atherosclerosis upon FXa inhibition, the effect on pre-existing plaques has never been studied. Therefore, we investigated effects of FXa inhibition by rivaroxaban on both newly-formed and pre-existing atherosclerotic plaques in apolipoprotein-e deficient (ApoE-/-) mice. Female ApoE-/- mice (age: 8-9 weeks, n = 10/group) received western type diet (WTD) or WTD supplemented with rivaroxaban (1.2 mg/g) for 14 weeks. In a second arm, mice received a WTD for 14 weeks, followed by continuation with either WTD or WTD supplemented with rivaroxaban (1.2 mg/g) for 6 weeks (total 20 weeks). Atherosclerotic burden in aortic arch was assessed by haematoxilin &amp; eosin immunohistochemistry (IHC); plaque vulnerability was examined by IHC against macrophages, collagen, vascular smooth muscle cells (VSMC) and matrix metalloproteinases (MMPs). In addition, PAR1 and -2 expressions and their main activators thrombin and FXa in the plaque were determined in the plaque. Administration of rivaroxaban at human therapeutic concentrations reduced the onset of atherosclerosis (-46%, p &lt; 0.05), and promoted a regression of pre-existing plaques in the carotids (-24%, p &lt; 0.001). In addition, the vulnerability of pre-existing plaques was reduced by FXa inhibition as reflected by reduced macrophages (-39.03%, p &lt; 0.05), enhanced collagen deposition (+38.47%, p &lt; 0.05) and diminished necrotic core (-31.39%, p &lt; 0.05). These findings were accompanied with elevated vascular smooth muscle cells and reduced MMPs. Furthermore, expression of PARs and their activators, thrombin and FXa was diminished after rivaroxaban treatment. Pharmacological inhibition of FXa promotes regression of advanced atherosclerotic plaques and enhances plaque stability. These data suggest that inhibition of FXa may be beneficial in prevention and regression of atherosclerosis, possibly mediated through reduced activation of PARs. 

Retracted: No

PubPeer comments:
 A micrograph in Figure 2 (14 wks Rivaroxaban, top row) and a micrograph in Figure 4A (14 weeks controls) are more similar than you would expect.  ,