Parenteral administration of factor Xa/IIa inhibitors limits experimental aortic aneurysm and atherosclerosis

Moran, Corey S., Seto, Sai-Wang, Krishna, Smriti M., Sharma, Surabhi, Jose, Roby J., Biros, Erik, Wang, Yutang, Morton, Susan K., and Golledge, Jonathan (2017) Parenteral administration of factor Xa/IIa inhibitors limits experimental aortic aneurysm and atherosclerosis. Scientific Reports, 7. 43079. pp. 1-12.

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Intraluminal thrombus is a consistent feature of human abdominal aortic aneurysm (AAA). Coagulation factor Xa (FXa) catalyses FII to thrombin (FIIa). We examined the effect of FXa/FIIa inhibition on experimental aortic aneurysm in apolipoprotein E-deficient (ApoE−/−) mice infused with angiotensin II (AngII). The concentration of FXa within the supra-renal aorta (SRA) correlated positively with SRA diameter. Parenteral administration of enoxaparin (FXa/IIa inhibitor) and fondaparinux (FXa inhibitor) over 14 days reduced to severity of aortic aneurysm and atherosclerosis in AngII-infused ApoE−/− mice. Enteral administration of the FIIa inhibitor dabigatran had no significant effect. Aortic protease-activated receptor (PAR)-2 expression increased in response to AngII infusion. Fondaparinux reduced SRA levels of FXa, FIIa, PAR-2, matrix metalloproteinase (MMP)2, Smad2/3 phosphorylation,and MOMA-2 positive cells in the mouse model. FXa stimulated Smad2/3 phosphorylation and MMP2 expression in aortic vascular smooth muscle cells (VSMC) in vitro. Expression of MMP2 in FXastimulated VSMC was downregulated in the presence of a PAR-2 but not a PAR-1 inhibitor. These findings suggest that FXa/FIIa inhibition limits aortic aneurysm and atherosclerosis severity due to down-regulation of vascular PAR-2-mediated Smad2/3 signalling and MMP2 expression. Inhibition of FXa/FIIa may be a potential therapy for limiting aortic aneurysm.

Item ID: 48093
Item Type: Article (Research - C1)
ISSN: 2045-2322
Keywords: abdominal aortic aneurysm; mouse model; factor Xa; factor IIa; anticoagulants
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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit © The Author(s) 2017.

Funders: National Institute of Health (NIH), National Health and Medical Research Council (NHMRC), Queensland Government
Projects and Grants: NHMRC 1022752, 1021416, 1020955, 1003707, 1000967 & 1019921
Date Deposited: 29 Mar 2017 01:50
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3201 Cardiovascular medicine and haematology > 320101 Cardiology (incl. cardiovascular diseases) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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