PPARγagonist Inhibited the Expression of β-Catenin in Rabbit Abdominal Aortic Artery Atherosclerotic Plaque with Hypercholesterolemia.

Objective: Atherosclerosis is a chronic inflammatory process; it involved T lymphoid cells and mono-macrophages adhesived and migrated to under endothelium, after phagocytosing LDL-cholesterol and become foam-cells. Moreover, T cells and macrophages secrets matrix metalloproteinase then promote smooth muscle cells migrating to beneath endothelium; and smooth muscle cells differentiated, proliferated and secreted extracellular matrix to form atherosclerotic plaque. All these factors resulted to vascular remodeling and atherosclerotic plaque formation. β-catenin is a important signal protein involved in controlling VSMC differentiation, proliferation, and fate, which can move to the nucleus, where it forms a complex with the TCF/LEF transcription factors to drive their target genes such as C-myc and cyclin D1, Cyclin D1 contains a Tcf response element within its promoter region and is thought to be a rate-limiting mediator of the G1 to S phase transition in the cell cycle. PPARagonist has been reported to inhibit mouse artery intima proliferation after balloon injury, moreover, PPARγagonists could have anti-atherosclerosis development in animal models, and also they could decrease the thickness of intima-media of carotid artery in patients with diabetes mellitus. In this research, we are aimed to investigate if PPARγagonist could inhibit the artery remodeling with hypercholesterolemia and vascular injury, in addition with the expression of β-catenin in remodeling artery.

Methods: 12 New Zealand male rabbits weighting 2 to 2.5 kg were given hypercholesterol chows for 2 weeks, and then catheter balloon injury was performed in the rabbit abdominal aortic artery. all rabbits were randomized to model group and rosiglitazone group, hypercholesterol chows were continued to give to all rabbits for another 4 weeks, and rosiglitazone group was given rosiglitazone 3mg/kg/d for 4 weeks. Animals were euthanized by pentobarbital overdose at 28 days after balloon injury. Abdominal arteries were harvested. Immunohistochemical analysis, reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to detect the expression of β-catenin in rabbit abdominal aortic artery.

Results: The thickness of intima-media in rosiglitazone group were significantly decreased than in hypercholesterolemia model group (1.048±0.076 vs 0.689±0.203mm p<0.001), also there were much less foam cells in atherosclerotic plaque in rosiglitazone group compared with hypercholesterolemia model group. Immunohistochemical analysis showed that there were many smooth muscle cells migrated and proliferated in the neointimal of remodeling artery, and there was much less stain for β-catenin in rosiglitazone group than in hypercholesterolemia model group. And both RT-PCR and western blot showed that the expression of mRNA and protein of β-catenin were significantly decreased in rosiglitazone group compared with hypercholesterolemia model group.

Conclusion: Hypercholesterolemia and vascular balloon injury are two important factors for smooth muscle cells migration and proliferation from medial; β-catenin expressed in the neointimall and might promote the formation of atherosclerosis; PPARγagonist not only inhibited the thickness of atherosclerotic plaque, but also significantly inhibited the expression of β-catenin; it might imply that the anti-atherosclerosis mechanism of PPARγ agonist may involve with β-catenin pathway.