title: Parenteral administration of factor Xa/IIa inhibitors limits experimental aortic aneurysm and atherosclerosis.
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.
authors.affiliation: Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, 4811, Australia.
authors.forename: Corey S
authors.initials: CS
authors.lastname: Moran
authors.affiliation: National Institute of Complementary Medicine, Western Sydney University, Campbelltown, 2560, Australia.
authors.forename: Sai-Wang
authors.initials: SW
authors.lastname: Seto
authors.affiliation: Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, 4811, Australia.
authors.forename: Smriti M
authors.initials: SM
authors.lastname: Krishna
authors.affiliation: Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, 4811, Australia.
authors.forename: Surabhi
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, 4811, Australia.
authors.forename: Roby J
authors.initials: RJ
authors.lastname: Jose
authors.affiliation: Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, 4811, Australia.
authors.forename: Erik
authors.initials: E
authors.lastname: Biros
authors.affiliation: School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia, Mount Helen, 3350, Australia.
authors.forename: Yutang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, 4811, Australia.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Morton
authors.affiliation: Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, 4811, Australia.|Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, 4814, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Golledge
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001014:Aortic Aneurysm / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D065427:Factor Xa Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation; D007263:Infusions, Parenteral; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D051379:Mice; D000074085:Mice, Knockout, ApoE; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors
chemical_list: D000991:Antithrombins; D065427:Factor Xa Inhibitors; D044464:Receptor, PAR-2; D051899:Smad2 Protein; D051900:Smad3 Protein; D013917:Thrombin; D020778:Matrix Metalloproteinase 2