Apolipoprotein A-I Mimetic Peptides Prevent Atherosclerosis Development and Reduce Plaque Inflammation in a Murine Model of Diabetes

OBJECTIVE: To determine the effect of the apolipoprotein A-I (ApoA-I) mimetic peptide, D-4F, on atherosclerosis development in a pre-existing diabetic condition. RESEARCH DESIGN AND METHODS: We induced hyperglycemia in 6-week-old apoE(−/−) female mice using streptozotocin. Half of the diabetic apoE(−/−) mice received D-4F in drinking water. Ten weeks later, plasma lipids, glucose, insulin levels, atherosclerotic lesions, and lesion 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 with nondiabetic 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, percentage of whole aorta, P < 0.01) and in aortic roots (36,038 ± 18,467 μm(2)/section vs. 17,998 ± 12,491 μm(2)/section, P < 0.01) when compared with 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 with nontreated animals (78.03 ± 26.1 vs. 29.6 ± 15.2 P < 0.001, percentage of whole plaque). There were no differences in glucose, insulin, total cholesterol, HDL cholesterol, and triglyceride levels between the two groups. Arachidonic acid, PGE(2), PGD(2), 15-HETE, 12-HETE, and 13-HODE concentrations were significantly increased in the liver tissue of diabetic apoE(−/−) mice compared with nondiabetic apoE(−/−) mice and significantly reduced by D-4F treatment. CONCLUSIONS: Our results suggest that oral D-4F can prevent atherosclerosis development in pre-existing diabetic mice and this is associated with a reduction in hepatic arachidonic acid and oxidized fatty acid levels.