Abstract

Objective To investigate the effect of down-regulation fibroblast growth factor 21 (FGF21) expression on atherosclerosis in diabetic apolipoproteins E deficient (ApoE-/-) mice. Methods Intraperitoneal injection of streptozotocin (STZ) was used to make diabetic ApoE-/- animal model. 8-week-old male C57 mice were used as normal control (n=8). ApoE-/- mice with the same age were randomly divided into 4 groups: ApoE-/- group, STZ-ApoE-/- group, STZ-ApoE-/-+ FGF21 Scramble miRNA (vehicle control) group, STZ-ApoE-/-+FGF21 miRNA group. FGF21 Scrambled siRNA and FGF21 miRNA were administered to mice by caudal vein at a dose of 3×109 pfu for each injection, once a week for 8 weeks (n=8). Blood glucose and lipid were determined with glucose oxidase method and enzymic method respectively. The serum level of FGF21 was detected by enzyme linked immunosorbent assay. The intima lipid deposit and the area of atherosclerosis plaque of thoracic aorta were detected by oil red O staining and hematoxylin-eosin (HE) staining respectively. Hepatocytes were cultured and treated with high glucose (25 mmol/L). Real-time polymerase chain reaction and western blotting were performed to measure FGF21 expression. All analysis were performed using SPSS 13.0 statistical software. Statistical significances among groups were evaluated by one-way analysis of variance (One-Way ANOVA) and pairwise comparision with LSD-t test. Results High glucose contributed to the expression of FGF21 in a time-dependent manner. Compared with ApoE-/- group, the level of fasting blood glucose, serum FGF21, liver FGF21 mRNA and protein were significantly increased in STZ-ApoE-/- group [(17.8±2.3) vs (7.5±0.7) mmol/L, t=-10.7, P<0.01; 129.59±15.35 vs 12.85±2.61, t=-18.4, P<0.01; 1.05±0.13 vs 20.36±3.02, t=-15.7, P<0.01; 1.30±0.14 vs 0.33±0.04, t=-16.8, P<0.01]. Compared with STZ-ApoE-/- group, the levels of liver FGF21 mRNA and protein were significantly decreased in STZ-ApoE-/-+FGF21 miRNA group (2.15±0.35 vs 20.36±3.02, t=-15.7, P<0.01; 0.36±0.04 vs 1.30±0.14, t=-16.8, P<0.01). Meanwhile, the fasting blood glucose, intima lipid deposit and the area of atherosclerosis plaque of thoracic aorta were significantly increased in STZ-ApoE-/-+FGF21 miRNA group [(23.2±2.3) vs (17.8±2.3) mmol/L, t=-3.85, P<0.01; 252±20 vs 176±14, t=-8.16, P<0.01]. Conclusion High glucose increased mRNA and protein levels of FGF21 in hepatocytes. FGF21 miRNA promotes the formation and development of arteriosclerosis in diabetic ApoE-/- mice, possibly through down-regulation of FGF21 expression. Key words: Diabetes mellitus; Dyslipidemias; Atherosclerosis; Apolipoproteins E; Fibroblast growth factor 21

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