- Title
- Parenteral administration of factor Xa/IIa inhibitors limits experimental aortic aneurysm and atherosclerosis
- Creator
- Moran, Corey; Seto, Sai-Wang; Krishna, Smriti; Sharma, Surabhi; Jose, Roby; Biros, Erik; Wang, Yutang; Morton, Susan; Golledge, Jonathan
- Date
- 2017
- Type
- Text; Journal article
- Identifier
- http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/155195
- Identifier
- vital:11278
- Identifier
-
https://doi.org/10.1038/srep43079
- Identifier
- ISBN:2045-2322
- Abstract
- 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 FXa-stimulated 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. © The Author(s) 2017.
- Publisher
- Nature Publishing Group
- Relation
- Scientific Reports Vol. 7, no. (2017), p. 1-12
- Rights
- Copyright © The Author(s) 2017. 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
- Rights
- Open Access
- Rights
- This metadata is freely available under a CCO license
- Subject
- Aortic aneurysm; Atherosclerosis; FXa/Flla inhibition
- Full Text
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