title: Novel Apo E-Derived ABCA1 Agonist Peptide (CS-6253) Promotes Reverse Cholesterol Transport and Induces Formation of preβ-1 HDL In Vitro.
abstract: Apolipoprotein (apo) mimetic peptides replicate some aspects of HDL function. We have previously reported the effects of compound ATI-5261 on its ability to replicate many functions of native apo A-I in the process of HDL biogenesis. ATI-5261 induced muscle toxicity in wild type C57Bl/6 mice, increased CPK, ALT and AST and increase in triglyceride (Tg) levels. Aromatic phenylalanine residues on the non-polar face of ATI-5261, together with positively charged arginine residues at the lipid-water interface were responsible for these effects. This information was used to create a novel analog (CS-6253) that was non-toxic. We evaluated this peptide designed from the carboxyl terminus of apo E, in its ability to mimic apo A-I functionality. Our data shows that the lipidated particles generated by incubating cells overexpressing ABCA1 with lipid free CS-6253 enhances the rate of ABCA1 lipid efflux with high affinity interactions with native ABCA1 oligomeric forms and plasma membrane micro-domains. Interaction between ABCA1 and lipid free CS-6253 resulted in formation of nascent HDL-CS-6253 particles that are actively remodeled in plasma. Mature HDL-CS-6253 particles deliver cholesterol to liver cells via SR-BI in-vitro. CS-6253 significantly increases cholesterol efflux in murine macrophages and in human THP-1 macrophage-derived foam cells expressing ABCA1. Addition of CS-6253 to plasma dose-dependently displaced apo A-I from α-HDL particles and led to de novo formation of preβ-1 HDL that stimulates ABCA1 dependent cholesterol efflux efficiently. When incubated with human plasma CS-6253 was also found to bind with HDL and LDL and promoted the transfer of cholesterol from HDL to LDL predominantly. Our data shows that CS-6253 mimics apo A-I in its ability to promote ABCA1-mediated formation of nascent HDL particles, and enhances formation of preβ-1 HDL with increase in the cycling of apo A-I between the preβ and α-HDL particles in-vitro. These mechanisms are potentially anti-atherogenic.
authors.affiliation: Cardiovascular Research Laboratories Laboratory, Research Institute of the McGill University Health Centre, Montréal, Québec H4A 3J1, Canada.
authors.forename: Anouar
authors.initials: A
authors.lastname: Hafiane
authors.affiliation: Lawrence Berkeley National Laboratory, Donner Laboratory, MS1-267, Berkeley, CA, United States of America.
authors.forename: John K
authors.initials: JK
authors.lastname: Bielicki
authors.affiliation: Artery Therapeutics, San Ramon, CA, United States of America.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Johansson
authors.affiliation: Cardiovascular Research Laboratories Laboratory, Research Institute of the McGill University Health Centre, Montréal, Québec H4A 3J1, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Genest
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001057:Apolipoproteins E / Q000737:chemistry / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D018955:CD36 Antigens / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005487:Foam Cells / Q000378:metabolism; D053442:High-Density Lipoproteins, Pre-beta / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D013997:Time Factors
chemical_list: C585585:ATI-5261; D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D018955:CD36 Antigens; C000607327:CS-6253; D053442:High-Density Lipoproteins, Pre-beta; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010743:Phospholipids; D002784:Cholesterol