Oral D-4F causes formation of pre-β high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice

• Published in: Circulation (New York, N.Y.) N.Y.), 2004-06, Vol.109 (25), p.3215-3220
• Main Authors: NAVAB, Mohamad, ANANTHARAMAIAH, G. M, FOGELMAN, Alan M, REDDY, Srinivasa T, HAMA, Susan, HOUGH, Greg, GRIJALVA, Victor R, WAGNER, Alan C, FRANK, Joy S, DATTA, Geeta, GARBER, David
• Format: Article
• Language: English
• Subjects: Administration, Oral; Amino Acid Sequence; Animals; Apolipoprotein A-I - pharmacology; Apolipoprotein A-I - therapeutic use; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Arteriosclerosis - blood; Arteriosclerosis - genetics; Aryldialkylphosphatase - blood; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Biological Transport - drug effects; Blood and lymphatic vessels; Blood coagulation. Blood cells; Cardiology. Vascular system; Cells, Cultured; Chemotaxis - drug effects; Cholesterol - metabolism; Coculture Techniques; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Drug Evaluation, Preclinical; Female; Fundamental and applied biological sciences. Psychology; High-Density Lipoproteins, Pre-beta; Humans; Hyperlipoproteinemia Type II - blood; Hyperlipoproteinemia Type II - genetics; Inflammation; Lipid Peroxidation - drug effects; Lipoproteins, HDL - biosynthesis; Lipoproteins, HDL - blood; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular and cellular biology; Molecular Sequence Data; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; Platelet
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000134275.90823.87

These studies were designed to determine the mechanism of action of an oral apolipoprotein (apo) A-I mimetic peptide, D-4F, which previously was shown to dramatically reduce atherosclerosis in mice. Twenty minutes after 500 microg of D-4F was given orally to apoE-null mice, small cholesterol-containing particles (CCPs) of 7 to 8 nm with pre-beta mobility and enriched in apoA-I and paraoxonase activity were found in plasma. Before D-4F, both mature HDL and the fast protein liquid chromatography fractions containing the CCPs were proinflammatory. Twenty minutes after oral D-4F, HDL and CCPs became antiinflammatory, and there was an increase in HDL-mediated cholesterol efflux from macrophages in vitro. Oral D-4F also promoted reverse cholesterol transport from intraperitoneally injected cholesterol-loaded macrophages in vivo. In addition, oral D-4F significantly reduced lipoprotein lipid hydroperoxides (LOOH), except for pre-beta HDL fractions, in which LOOH increased. The mechanism of action of oral D-4F in apoE-null mice involves rapid formation of CCPs, with pre-beta mobility enriched in apoA-I and paraoxonase activity. As a result, lipoprotein LOOH are reduced, HDL becomes antiinflammatory, and HDL-mediated cholesterol efflux and reverse cholesterol transport from macrophages are stimulated.