Abstract 393: Lipoprotein Inflammatory Properties But Not Cholesterol Levels Predict Lesion Area in Cholesterol-fed Rabbits
Recent reports have suggested that the inflammatory properties of HDL may predict susceptibility to atherosclerosis in mice and humans better than HDL-cholesterol levels. To directly test the importance of lipoprotein cholesterol levels versus their inflammatory properties in an animal model of atherosclerosis, we studied cholesterol-fed rabbits that were sham-treated or treated with an apolipoprotein A-I (apoA-I) mimetic peptide (4F) previously shown to have potent anti-atherosclerotic and vasoprotective properties in mouse and rat models of atherosclerosis and diabetes respectively. After 1 month on a 1% cholesterol diet, daily subcutaneous injections of vehicle, or apolipoprotein A-I mimetic peptides synthesized from D- (D-4F), or L-amino acids (L- 4F) at 10 mg/kg day were started in rabbits. A month later plasma cholesterol levels, (mg/dL) were (Mean +/− S.D.) 1590 +/− 382 (vehicle), 1292 +/−317 (D-4F), and 1148 +/− 247 (L-4F). The percent of aorta (Mean +/− S.D.) with atherosclerotic lesions was 24 +/− 15% (vehicle), 10 +/− 6% (D-4F), and 13 +/− 9% (L-4F). Inflammatory indices for HDL and LDL were determined by measuring monocyte chemotactic activity after adding rabbit lipoproteins to human endothelial cells. The HDL-inflammatory index (HII) and LDL-inflammatory index (LII), respectively, were 1.39 +/− 0.24; 1.35 +/− 0.29 (vehicle), 0.67 +/− 0.26; 0.63 +/− 0.38 (D-4F), and 0.67 +/− 0.2; 0.68 +/− 0.32 (L-4F) (Mean +/− S.D.). There was no correlation between lesions and total plasma, HDL or LDL cholesterol levels. In contrast, there was a positive correlation with HII and LII (p = 0.002 and p = 0.0026, respectively). We conclude that D-4F and L-4F are equally efficacious in cholesterol-fed rabbits in improving HII and LII and decreasing aortic lesions. To our knowledge this is the first rabbit lesion study to be reported with this class of peptides (class A amphipathic helical peptides), the first study to directly compare the ability of the same peptide synthesized from all D-amino acids (D-4F) versus all L-amino acids (L-4F) to alter atherosclerosis, and the first study to directly compare lipoprotein inflammatory properties versus cholesterol concentrations as predictors of atherosclerotic lesions.