title: Enhancement by LDL of transfer of L-4F and oxidized lipids to HDL in C57BL/6J mice and human plasma.
abstract: The apoA-I mimetic peptide L-4F [(Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2) synthesized from all L-amino acids] has shown potential for the treatment of a variety of diseases. Here, we demonstrate that LDL promotes association between L-4F and HDL. A 2- to 3-fold greater association of L-4F with human HDL was observed in the presence of human LDL as compared with HDL by itself. This association further increased when LDL was supplemented with the oxidized lipid 15S-hydroxy-5Z, 8Z, 11Z, 13E-eicosatetraenoic acid (15HETE). Additionally, L-4F significantly (P = 0.02) promoted the transfer of 15HETE from LDL to HDL. The transfer of L-4F from LDL to HDL was demonstrated both in vitro and in C57BL/6J mice. L-4F, injected into C57BL/6J mice, associated rapidly with HDL and was then cleared quickly from the circulation. Similarly, L-4F loaded onto human HDL and injected into C57BL/6J mice was cleared quickly with T(1/2) = 23.6 min. This was accompanied by a decline in human apoA-I with little or no effect on the mouse apoA-I. Based on these results, we propose that i) LDL promotes the association of L-4F with HDL and ii) in the presence of L-4F, oxidized lipids in LDL are rapidly transferred to HDL allowing these oxidized lipids to be acted upon by HDL-associated enzymes and/or cleared from the circulation.
authors.affiliation: Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Meriwether
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imaizumi
authors.forename: Victor
authors.initials: V
authors.lastname: Grijalva
authors.forename: Greg
authors.initials: G
authors.lastname: Hough
authors.forename: Ladan
authors.initials: L
authors.lastname: Vakili
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
authors.forename: Robin
authors.initials: R
authors.lastname: Farias-Eisner
authors.forename: Mohamad
authors.initials: M
authors.lastname: Navab
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
authors.forename: Srinivasa T
authors.initials: ST
authors.lastname: Reddy
authors.forename: Ishaiahu
authors.initials: I
authors.lastname: Shechter
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D016632:Apolipoprotein A-I; D006893:Hydroxyeicosatetraenoic Acids; C472885:L-4F peptide; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D010455:Peptides; C099252:oxidized low density lipoprotein; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid