Objective To study the effects of β₃-adrenoceptor (β₃-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 β₃-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 β₃-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 (P₃-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 β₃-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 β₃-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 β₃-AR antagonist SR52390A did not affect any parameters (P > 0.05 for all measures vs. ApoE^-/- mice receiving vehicle).

Conclusions β₃-AR agonist impeded the progression of atherosclerosis in ApoE^-/- mice, possibly through improvement of lipid profile, ApoA-I, ApoA-II and SR-BI mRNA.