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CHOLESTYRAMINE PERINATAL TREATMENT OF APOE DEFICIENT MICE REDUCES ATHEROSCLEROTIC PLAQUES DEVELOPMENT IN ADULT OFFSPRING.
Abstract
Background and Aims
We have shown that ApoE-/- mice born to hypercholesterolemic ApoE-/- mothers develop more atherosclerotic plaques than ApoE-/- mice born to normocholesterolemic ApoE+/- mothers. We aimed to investigate the effect of treatment with a cholesterol-lowering drug in ApoE-/- mice during gestation only or during both gestation and lactation on the development of atherosclerosis in adult ApoE-/- offspring.
Methods
Three groups of ApoE-/- females were fed either control diet (CTR), a diet with 3% cholestyramine during gestation (CTY-G) or during gestation and lactation (CTY-GL). At 25 weeks of age, males and females offspring were sacrificed and the size of atherosclerotic plaques in the aortic roots was measured. Plasma cholesterol, triglycerides and bile acids concentrations were determined. MicroRNA expression in liver were analysed.
Results
A significant reduction in atherosclerotic plaque area was observed in male progeny of CTY-G and CTY-GL, at 600µm from the heart (p= 0.01 and p=0.02 respectively) and at 800µm. Plaque regression is also observed in females at 600 m for CTY-G (p=0,006) and at 800 μm for CTY-GL (p=0.03). Neither cholesterolemia nor triglyceridemia showed any significant difference between groups. In male CTY-GL offspring and female CTY-G and CTY-GL, significant increase in the plasma tauro-conjugated bile acids pools was noted (p=0.03, p=0.01 and p=0.04 respectively). Among analyzed microRNA, hepatic miR122 expression decreased significantly in male CTY-G and female CTY-GL (p=0.01).
Conclusions
Cholestyramine perinatal treatment decreases atherosclerosis development in offspring. This effect is independent of the cholesterol levels. The bile acids pools increase and mi-RNA 122 decrease could explain the protective effect of treatment.