Effects of the factor Xa inhibitor, fondaparinux, on the stability of atherosclerotic lesions in apolipoprotein E-deficient mice.
BACKGROUND
Atherosclerosis is a progressive inflammatory disease that can lead to sudden cardiac events by plaque rupture and subsequent thrombosis. Factor Xa (FXa) not only occupies a crucial position in the coagulation cascade responsible for thrombin generation, but also has pro-inflammatory effects. The hypothesis that Fondaparinux, the selective FXa inhibitor, attenuates plaque progression and promotes stability of atherosclerotic lesions was assessed.


RESULTS
Fondaparinux (5 mg/kg body weight/day) or 0.9% saline was intraperitoneally administered for 4 weeks to apolipoprotein E-deficient mice (n=12 per group) with established atherosclerotic lesions in the innominate arteries. Fondaparinux did not remarkably decrease the progression of atherosclerosis development in apolipoprotein E-deficient mice, but increased the thickness of fibrous cap (P=0.049) and decreased the ratio of necrotic core (P=0.001) significantly. Moreover, Fondaparinux reduced the staining against Mac-2 (P=0.017), α-SMA (P=0.002), protease-activated receptor (PAR)-1 (P=0.001), PAR-2 (P=0.003), CD-31 (P=0.024), MMP-9 (P=0.000), MMP-13(P=0.011), VCAM-1 (P=0.041) and the mRNA expression of inflammatory mediators (P<0.05) significantly, such as interleukin (IL)-6, MCP-1, IFN-γ, TNF-α, IL-10 and Egr-1.


CONCLUSIONS
Fondaparinux, the selective FXa inhibitor, can promote the stability of atherosclerotic lesions in apolipoprotein E-deficient mice, possibly through inhibiting expression of the inflammatory mediators in plaque and reduced synthesis of MMP-9 and MMP-13.
Department of Cardiology, Zhongda Hospital, Medical School of Southeast University.
Pengfei
P
Zuo
Qianxing
Q
Zhou
Zhi
Z
Zuo
Xin
X
Wang
Long
L
Chen
Genshan
G
Ma
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001777:Blood Coagulation / Q000187:drug effects; D016122:Brachiocephalic Trunk / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors / Q000494:pharmacology*; D005355:Fibrosis; D000077425:Fondaparinux; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D009336:Necrosis; D058226:Plaque, Atherosclerotic; D011134:Polysaccharides / Q000494:pharmacology*; D013997:Time Factors
D001057:Apolipoproteins E; D016207:Cytokines; D065427:Factor Xa Inhibitors; D018836:Inflammation Mediators; D011134:Polysaccharides; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D000077425:Fondaparinux