TY - JOUR
T1 - Targeting Coagulation Factor Xa Promotes Regression of Advanced Atherosclerosis in Apolipoprotein-E Deficient Mice
AU - Posthuma, Jelle J.
AU - Posma, Jens J. N.
AU - van Oerle, Rene
AU - Leenders, Peter
AU - van Gorp, Rick H.
AU - Jaminon, Armand M. G.
AU - Mackman, Nigel
AU - Heitmeier, Stefan
AU - Schurgers, Leon J.
AU - ten Cate, Hugo
AU - Spronk, Henri M. H.
N1 - Funding Information:
The author(s) would like to thank the volunteers and Diane Fens, Marie van der Walle, Patricia Pluijmen, Stefanie van Geleen and Rick Wetzels for technical support. The author(s) disclosed receipt of financial support for the research by Bayer Pharma AG. HtC is a Fellow of the Gutenberg Research College, Centre for Thrombosis and Haemostasis, Gutenberg University, Mainz, Germany. JNP is supported the Dutch Heart Foundation (CVON 2014-09, Reappraisal of Atrial Fibrillation: Interaction between HyperCoagulability, Electrical Remodeling, and Vascular Destabilization in the Progression of Atrial Fibrillation - RACE V). JJP is the recipient of a Kootstra Talent Fellowship from Maastricht University Medical Centre.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/3/7
Y1 - 2019/3/7
N2 - 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 & 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 <0.05), and promoted a regression of pre-existing plaques in the carotids (-24%, p <0.001). In addition, the vulnerability of pre-existing plaques was reduced by FXa inhibition as reflected by reduced macrophages (-39.03%, p <0.05), enhanced collagen deposition (+38.47%, p <0.05) and diminished necrotic core (-31.39%, p <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.
AB - 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 & 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 <0.05), and promoted a regression of pre-existing plaques in the carotids (-24%, p <0.001). In addition, the vulnerability of pre-existing plaques was reduced by FXa inhibition as reflected by reduced macrophages (-39.03%, p <0.05), enhanced collagen deposition (+38.47%, p <0.05) and diminished necrotic core (-31.39%, p <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.
KW - PROTEASE-ACTIVATED RECEPTORS
KW - DABIGATRAN ETEXILATE
KW - THROMBIN INHIBITION
KW - INFLAMMATION
KW - PROGRESSION
KW - STABILITY
KW - LESIONS
U2 - 10.1038/s41598-019-40602-w
DO - 10.1038/s41598-019-40602-w
M3 - Article
C2 - 30846818
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 3909
ER -