ABSTRACT: Fibrates are peroxisome proliferator-activated receptor alpha (PPARalpha) agonists which modulate many aspects of lipoprotein metabolism and inflammation. They have been recently demonstrated to inhibit in vitro expression of tissue factor (TF), the main initiator of blood coagulation, which probably plays a pivotal role in thrombotic complications after plaque rupture. We investigated whether a 4-week fenofibrate treatment might affect the TF expression and cellular modifications in angioplasty-induced rabbit plaque rupture.
After plaque rupture by balloon angioplasty in atheromatous rabbits, animals were randomized in an untreated group or a group receiving fenofibrate. The TF content of arterial wall and the histological modifications were analyzed after 4 weeks.
Fenofibrate decreased in vivo TF expression (-42%, P<.05) and plaque cholesterol content (P<.01) in iliac arteries. Fenofibrate significantly improved the reendothelialization process by 51% (P<.05) and modified cellular distribution in the plaque toward increased stabilization.
These data indicate that the PPARalpha-activator fenofibrate reduces plaque thrombogenicity and accelerates endothelial regrowth which, altogether, might improve plaque stability. These effects may underlie the preventive effects of fibrate therapy in atherosclerosis complications.
Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 04/2008; 18(3):140-7. · 1.63 Impact Factor
ABSTRACT: Aortic valve sclerosis (AVS) shares epidemiological and histological similarities with atherosclerosis. Tissue factor (TF), the main initiator of blood coagulation, is present in atherosclerotic plaques and contributes to their thrombogenicity. We aimed to analyze valvular TF expression in addition to other components of atherosclerosis in two models of AVS.
Forty-five rabbits were randomly assigned to receive either normal chow (Ctrl, n=15), or 1% cholesterol-enriched chow alone (Hyperchol, n=15) or associated with vitamin D(2) (VitD, n=15), for 12 weeks. Aortic valve (AV) performance, leaflet structure, cellular and lipid infiltration, and TF expression were assessed using Doppler, histology, and immunohistochemistry, respectively, and TF activity was evaluated in AV leaflets.
Hyperchol and VitD animals developed abnormal leaflet thickening, with a significant alteration of AV performance in VitD animals. Leaflet thickening was related to the development of fatty plaque neolesions on the aortic side of the leaflets, displaying extracellular matrix disorganization, lipid and cellular infiltration, and calcification in VitD animals. TF was found on the leaflet aortic side in Ctrl animals and was identified in AVS lesions in both Hyperchol and VitD animals. TF immunostaining area and valvular activity increased significantly across the three groups.
Experimental AVS lesions that are present on the aortic side of leaflets display numerous characteristics of vascular atherosclerosis, including TF expression. Identification of TF associated with other components of the atherosclerotic process in AVS lesions strengthens the link between atherosclerosis and AVS.
Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 04/2008; 18(2):67-76. · 1.63 Impact Factor
ABSTRACT: Tissue factor (TF), the main initiator of blood coagulation, is involved in cellular migration and angiogenesis processes. TF is expressed strongly in lipid-rich plaques and probably plays an important role in the thrombotic complications of plaque rupture. This study analyzes the effect of dietary lipid lowering on TF expression and cellular modifications in angioplasty-induced rabbit plaque rupture.
After experimental plaque rupture by balloon angioplasty in atheromatous rabbits, animals were assigned a 0.2% or a 2% cholesterol diet, and the TF content of arterial wall and the associated histological modifications were analyzed after 4 weeks. Early effects of lipid lowering were observed: The increase of TF expression in the vascular wall was stronger in the 2% than in the 0.2% cholesterol diet group (iliac arteries: 1226+/-308 versus 72+/-29 mU TF/g artery, P<0.005). Immunohistochemistry indicated that TF expression was associated with sprout of neovessels, which was more pronounced in the 2% than in the 0.2% cholesterol group.
This study shows that dietary lipid lowering decreases the thrombotic potential of ruptured atherosclerotic plaques through TF decrease. Moreover, high TF expression is associated with marked angiogenesis in the vascular wall, which is reduced by lipid lowering. These results provide further arguments for strong dietary lipid lowering to reduce plaque instability and thrombogenicity.
Circulation 10/2003; 108(14):1740-5. · 14.74 Impact Factor