Abstract 1335: Rosuvastatin Increases Insulin Sensitivity and Reduces Atherosclerotic Plaque Volume and Plaque Macrophage and Oxidized LDL Content in Obese Dyslipidemic Mice in the Absence of Cholesterol Reduction
Background Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase ameliorate atherosclerotic diseases. We investigated the effect of rosuvastatin on plaque volume and composition in the aortic arch of mice with combined leptin and LDL-receptor deficiency (DKO). In DKO mice, obesity, diabetes and hyperlipidemia are associated with increased oxidative stress and accelerated atherosclerosis.
Methods and Results Twelve-week old DKO were treated with rosuvastatin (10 mg/kg/day, s.c.) (N=10) or placebo (N=11) for 12 weeks. Rosuvastatin lowered triglycerides (254±156 vs. 477±136 mg/dL for placebo; P<0.01), FFA (0.16±0.06 vs. 0.56±0.15 mmol/L, P<0.05) and HOMA (836±461 vs. 1812±735; P<0.01) in the absence of an effect on total cholesterol (552±254 vs. 564±89 mg/dL). In white adipose tissue RT-PCR analysis showed that rosuvastatin increased the RNA expression (% versus lean mice) of PPARα (36±15 vs. 15±9%, P<0.01) and FATP4 (48±8 vs. 37±6%; P<0.05) which were associated with the decrease in FFA and the increase in insulin sensitivity. Rosuvastatin lowered the volume (0.029±0.036 vs. 0.086±0.043 mm3), the macrophage (22±4 vs. 35±7 %), lipid (16±3 vs. 39±8 %) and oxLDL area (14±9 vs. 54±13 %), and the oxLDL-to-LDL ratio (52±25 vs. 137±49) of plaques in the aortic arch (all P<0.01). Upregulation of PPARγ (79±35 vs. 40±10 %; P<0.01) and downstream genes CD36 (96±34 vs. 56±17 %; P<0.05) and ABCA1 (113±36 vs. 76±10 %; P<0.05) in aortic extracts of rosuvastatin-treated mice was associated with a reduction of plaque oxLDL and lipids. Upregulation of plaque PPARγ was also associated with an increase in SOD1 RNA (79±30 vs. 45±7%; P<0.01) and protein (22±6 vs. 8±4%; P<0.01) in rosuvastatin-treated mice. Indeed, SOD1 expression was the strongest independent predictor of oxLDL levels (R2=0.53, P=0.001).
Conclusions Rosuvastatin-associated increase in PPARα in adipose tissue is associated with increased insulin sensitivity. A similar association between PPARα and HOMA was seen in DKO mice after weight loss and treatment with a dual PPARα/γ agonist. Rosuvastatin-associated increase in PPARγ in the aortic arch was associated with an increased expression of SOD1, CD36 and ABCA1, which was associated with a decrease in plaque oxLDL and lipids.