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: Corey S Moran, Sai-Wang Seto, Smriti M Krishna, Surabhi Sharma, Roby J Jose, Erik Biros, Yutang Wang, Susan K Morton, Jonathan Golledge
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 43079 (02 21 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28220880 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antithrombins
• Factor Xa Inhibitors
• Receptor, PAR-2
• Smad2 Protein
• Smad3 Protein
• Thrombin
• Matrix Metalloproteinase 2

Topics

• Animals
• Antithrombins (administration & dosage, pharmacology, therapeutic use)
• Aortic Aneurysm (drug therapy, metabolism, prevention & control)
• Atherosclerosis (drug therapy, metabolism, prevention & control)
• Disease Models, Animal
• Factor Xa Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Gene Expression Regulation
• Infusions, Parenteral
• Male
• Matrix Metalloproteinase 2 (genetics)
• Mice
• Mice, Knockout, ApoE
• Receptor, PAR-2 (genetics, metabolism)
• Signal Transduction
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Thrombin (antagonists & inhibitors)