ASSA13-03-17 b3-Adrenoceptor Activation Improves the Formation of Atherosclerosis Plaque in Aged ApoE-Deficient Mice

Abstract

Objective To study the effects of β 3 -adrenoceptor (β 3 -AR) activation on atherosclerotic plaque development in aged apolipoprotein E-deficient (ApoE -/- ) mice. Methods Male ApoE -/- mice were fed with a high-fat diet, starting on 10 weeks of age. Starting from 36 weeks of age, mice were randomly treated with atorvastatin (10 mg · kg -1 ·d -1 , by gavage), the β 3 -AR agonist BRL37344 (1.65 or 3.30 μg·kg -1 , twice a week, by intraperitoneal injection), the β3-AR antagonist SR52390A (50 μg·kg -1 , twice a week, by intraperitoneal injection), or saline vehicle (twice a week, by intraperitoneal injection) for 12 weeks (n = 10 per group). A group of wild-type C57BL/6J mice receiving normal diet was included as a healthy control. At the end of the 12-week treatment period, serum concentration of lipids were measured. Atherosclerotic plaque in the thoracic aorta was examined using Hematoxy-eosin staining. The extent of fibrosis in the plaque was examined using Masson staining. Western blot was uesed to determine the ApoA-I and SR-BI protein expression. Real-time quantitative PCR was used to determine β 3 -AR mRNA in the white adipose tissue and the ApoA-I, ApoA-II and SR-BI mRNA expression in liver tissue. Results High-fat diet in ApoE -/- mice led to hyperlipidemia and the area of and the extent of fibrosis in atherosclerotic plaque (P 3 -AR mRNA and SR-BI mRNA were lower, ApoA-I and ApoA-II mRNA were higher in ApoE -/- mice (P -/- mice receiving vehicle). Treatment with the β 3 -AR agonist BRL37344 decreased serum concentration of triglyceride, total cholesterol and non-high density lipoprotein cholesterol. The treatment increased high density lipoprotein cholesterol, downregulated of ApoA-I, ApoA-II and SR-BI expression and upregulated the β 3 -AR mRNA expression (P -/- mice receiving vehicle). Similar to atorvastatin, BRL37344 treatment dose-dependently reduced the plaque area and collagen content (P -/- mice receiving vehicle at a dose of 3.30 but not 1.65 μg·kg -1 ). Treatment with the β 3 -AR antagonist SR52390A did not affect any parameters (P > 0.05 for all measures vs. ApoE -/- mice receiving vehicle). Conclusions β 3 -AR agonist impeded the progression of atherosclerosis in ApoE -/- mice, possibly through improvement of lipid profile, ApoA-I, ApoA-II and SR-BI mRNA.