Objective To investigate the mechanism of inhibitory effect of CTLA-4Ig fusion protein on atherosclerosis in mice with an apolipoprotein-E gene defect fed on cholesterol diet.

Methods 30 male 10-week-old apoE(-/-) mice were fed on cholesterol diet and divided into CTLA-4Ig treatment group, IgG1 group and PBS group at random, 10 in each. The three groups were given intraperitoneal injection of CTLA-4Ig (10 μg per time), Rat-IgG1 (10 μg per time), (and) PBS (100 μl per time) respectively, twice a week, for 12 weeks. Followed by a 12-week treatment, the whole aorta from the root to crotch of iliac artery was separated after anaesthesia with the intraperitoneal injection of 1% pentobarbital and the whole (total) blood was taken to obtain serum. Subsequently, the area ratio of plaque and lumen, the thickness ratio of endangium and tunica media, the lipid-soaking extent intra-plaque and the content of collagen fibrils and smooth muscle cells intra-plaque were analysed by image-processing soft. The serum concentration of total cholesterol, CRP, sICAM-1, IFN-γ, IL-10, and TGF-β1 were measured.

Results There were typical atherosclerotic plaque in apoE(-/-) mice fed on cholesterol diet after 12 weeks and it was light in the CTLA-4Ig group. There were statistical value of difference in the area ratio of plaque and lumen, the thickness ratio of endangium and tunica media, the lipid-soaking extent intra-plaque, and the content of collagen fibrils in three groups (p all<0.05). It was found that the area ratio of plaque and lumen, the thickness ratio of endangium and tunica media, and the lipid-soaking extent intra-plaque were significant lower and the content of collagen fibrils was higher in the CTLA-4Ig group than those in the IgG1 group and PBS group (p all<0.05), but there was no significant difference in those between the IgG1 group and PBS group (p all>0.05). There were no significant difference in content of smooth muscle cells in three groups (p>0.05). There were no significant difference in serum concentration of total cholesterol in three groups (p>0.05). There were statistical value of difference in the serum concentration of CRP, sICAM-1, IFN-γ, IL-10, and TGF-β1 in all three groups (p all<0.05). It was found that CTLA-4Ig could decrease the serum concentration of CRP, sICAM-1 and IFN-γ and increase IL-10 and TGF-β1, but IgG1 and PBS.

Conclusions CTLA-4Ig fusion protein could inhibit the (del) atherosclerosis progression in apoE(-/-) mice fed on cholesterol diet and it's effect might be associated with blocking B7/CD28, anti-inflammation, promoting Th2 polarisation and affecting regulate T cells.