Effects of atorvastatin and/or probucol on recovery of atherosclerosis in high-fat-diet-fed apolipoprotein E-deficient mice.

ABSTRACT

INTRODUCTION: We have investigated the possible effects and mechanism of atorvastatin, a statin, and/or probucol, a powerful antioxidant used to lower cholesterol before 1995, on the atherosclerosis development. METHODS: Apolipoprotein-E-deficient (ApoE-/-) mice fed with the high fat diet were randomly divided into 3 groups (n = 10/each group) Placebo, Atorvastatin (10 mg/ kg/d), and atorvastatin (10 mg/kg/d) plus probucol (10 mg/kg/d) groups. C57BL/6 J mice were fed with normal diet as the control group (n = 10). Animals were sacrificed 10 weeks after the intervention. To evaluate the experimental atherosclerosis, blood tests were used for measuring serum lipoprotein profile, Western blots for endoplasmic reticulum (ER) stress protein expression, H&E staining for plaque lesions, immunohistology for macrophages, inflammatory cytokines, innate immune receptor TLR-4, transcription factor NF-κB, and atherosclerosis plaques. RESULTS: Compared with the control group, ApoE-/- mice in the placebo group showed with the significantly (p < 0.05) higher levels of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL) and oxidized low density lipoprotein (ox-LDL), PERK, GRP78, CHOP, IL-1ß, TNF-α and NF-κB, but with the lower levels of high-density lipoprotein cholesterol (HDL) and TLR-4, and also the increase in macrophages and the aortic media collagen, and the decrease in the elastic fibers (p < 0.01). Treatment with atorvastatin recovered all these features (p < 0.05 or p < 0.01) near to the levels in the control group. In addition, the combination of atorvastatin and probucol has shown the slightly stronger effect than the use of atorvastatin alone without statistical significances when comparing most bio-markers of atherosclerosis, but with significant differences in the reduction of the plaque lesion areas and macrophages (p < 0.05). CONCLUSIONS: Atorvastatin and/or probucol suppresses ER stress and increase the level of TLR-4, which lowers NF-κB, resulting in the recovery of atherosclerosis in the ApoE-/- mouse model.