Abstract 16088: ApoA-I Mimetic Peptide Prevents Atherosclerosis Development and Reduces Plaque Inflammation In A Mouse Model of Diabetes
Objective: The ApoA-I mimetic peptide, D-4F, drastically reduces atherosclerosis in ApoE-/- mice by a mechanism that is i) independent of plasma cholesterol levels and ii) in part related to its ability to remove oxidized lipids from lipoproteins. ApoA-I mimetic peptides were previously shown to increase antioxidants, confer robust vascular protection and improve insulin sensitivity in rodent models of diabetes and obesity. In the present study, we examined whether oral D-4F can inhibit atherosclerosis development in pre-existing diabetic conditions.
Methods: We induced hyperglycemia in six week-old ApoE-/- female mice using streptozotocin. Half of the diabetic ApoE-/- mice received D-4F in drinking water (1 mg/day, n=17). Ten weeks later, plasma lipids, glucose and insulin levels, atherosclerotic lesions, and lesional macrophage content, were measured.
Results: Diabetic ApoE-/- mice developed 300% more lesion area, marked dyslipidemia, increased glucose levels and reduced plasma insulin levels, when compared to non diabetic ApoE-/- mice. Atherosclerotic lesions were significantly reduced in the D-4F treated diabetic ApoE-/- mice in whole aorta (1.11±0.73 vs. 0.58±0.44, % whole aorta, p<0.01) and in aortic roots (36038±18467 μm2/section vs. 17998±12491μm2/section, P<0.01) when compared to diabetic ApoE-/- mice that did not receive D-4F. Macrophage content in atherosclerotic lesions from D-4F treated diabetic ApoE-/- mice was significantly reduced when compared to non-treated animals (29.6 ±15.2 vs 78.03±26.1 P<0.001, % of whole plaque). There were no differences in glucose, insulin, total cholesterol, HDL-cholesterol and triglycerides between the two groups of mice. 15-HETE, 12-HETE and 13-HODE concentrations were significantly increased in liver tissue of diabetic ApoE-/- mice. D-4F treated diabetic ApoE-/- mice showed reductions in hepatic content of 15-HETE (16.5±7.9 vs. 13.2±1.9 ng/ml, p=0.06), 12-HETE (31.1±16.1 vs. 16.1±6.8 ng/ml, p=0.05) and 13-HODE (155.0±76.2 vs. 109.9±21.8 ng/ml, p<0.05) when compared to diabetic ApoE-/- mice.
Conclusions: Our results suggest that oral D-4F can decrease atherosclerosis in diabetic mice by a mechanism that may involve reduction of oxidized fatty acids.
- © 2010 by American Heart Association, Inc.