d-4f-peptide and Arteriosclerosis

The effects of apolipoprotein (Apo) AI mimetic peptide synthesized from D- and L-amino acids on atherosclerotic lesion formation were investigated in low-density lipoprotein (LDL) receptor-deficient mice on a Western diet and in apoE null mice. In addition, their effects on the inflammatory changes induced in LDL-receptor mice fed a Western diet following influenza A infection were studied. When apolipoprotein AI mimetic peptides synthesized from either D- or L-amino acids were administered to LDL-receptor null mice, only peptides synthesized from D-amino acids were stable in the circulation and enhanced the ability of high-density lipoprotein (HDL) to protect LDL against oxidation. Administration of the peptide D-4F to LDL-receptor null mice and apoE null mice decreased lesion size. Additionally, in LDL receptor null mice after influenza infection, D-4F treatment increased plasma HDL levels and paraoxonase activity, and inhibited increased in LDL-cholesterol and peak levels of interleukin-6 post-infection. Injection of female mice with male macrophages, and subsequent measurement of the male 'sry' gene, revealed a marked increase in macrophage traffic into the aortic arch after infection that was prevented by administration of D-4F. This indicates that: (i) oral D-4F has powerful anti-atherosclerotic properties, and (ii) the loss of the anti-inflammatory properties of HDL after influenza infection in mice is associated with increased arterial macrophage traffic that can be prevented by administration of D-4F.

Topics: Animals; Apolipoprotein A-I; Arteriosclerosis; Cholesterol, HDL; Cholesterol, LDL; Disease Models, Animal; Humans; Influenza, Human; Receptors, LDL; Vasodilation

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.

Topics: Administration, Oral; Amino Acid Sequence; Animals; Apolipoprotein A-I; Apolipoproteins E; Arteriosclerosis; Aryldialkylphosphatase; Biological Transport; Cells, Cultured; Chemotaxis; Cholesterol; Coculture Techniques; Drug Evaluation, Preclinical; Female; High-Density Lipoproteins, Pre-beta; Humans; Hyperlipoproteinemia Type II; Inflammation; Lipid Peroxidation; Lipoproteins, HDL; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Monocytes

Apolipoprotein (apo) A-I and apoA-I-mimetic peptides showed promise to prevent atherosclerosis development. Using a bypassed vein graft model in apoE-null mice, we evaluated the effects of oral or intraperitoneal administration of an apoA-I-mimetic peptide on evolving atherosclerotic lesions in the vein graft and compared such effects on the established atherosclerotic lesions in aortic sinus in the same mice.. We used apoE-null mice in which a segment of inferior vena cava was grafted into the right carotid artery at 16 weeks of age. Native aortic atherosclerotic lesions (established atherosclerosis) and vein-graft atherosclerotic lesions (evolving atherosclerosis) were assessed 4 weeks after daily oral (0.3 mg/mL) or intraperitoneal (50 microg in 200 microL saline) administration of an apoA-I-mimetic peptide, D4F. Mice receiving saline or water without D4F served as controls. Both oral and intraperitoneal administration of D4F reduced vein-graft atherosclerotic (evolving lesions) plaque size by 43% and 42%, plaque lipid by 70% and 49%, and macrophage immunoreactivity by 63% and 62%, respectively, compared with controls. In contrast, D4F had no effect on the native aortic sinus atherosclerotic lesions (established lesions).. Oral and intraperitoneal administration of the apoA-I-mimetic peptide D4F significantly reduced rapidly evolving atherosclerotic lesions in vein grafts but not established atherosclerotic lesions in aortic sinus. These observations suggest that the type of atherosclerotic lesions and the time of initiation during the course of lesion evolution modulate the beneficial effects of apoA-I-mimetic peptides on atherosclerosis.

Topics: Administration, Oral; Amino Acid Sequence; Animals; Aortic Diseases; Apolipoprotein A-I; Apolipoproteins E; Arteriosclerosis; Blood Vessel Prosthesis; Body Weight; Carotid Arteries; Cell Count; Diet, Atherogenic; Graft Occlusion, Vascular; Hypercholesterolemia; Injections, Intraperitoneal; Lipids; Macrophages; Mice; Mice, Knockout; Molecular Sequence Data; Peptides; Serum Amyloid A Protein; Transplantation, Heterotopic; Vena Cava, Inferior