title: Apolipoprotein E derived HDL mimetic peptide ATI-5261 promotes nascent HDL formation and reverse cholesterol transport in vitro.
abstract: Modulation of the reverse cholesterol transport (RCT) pathway may provide a therapeutic target for the prevention and treatment of atherosclerotic cardiovascular disease (CVD). In the present study, we evaluated a novel 26-amino acid apolipoprotein mimetic peptide (ATI-5261) designed from the carboxyl terminal of apoE, in its ability to mimic apoA-I functionality in RCT in vitro. Our data shows that nascent HDL-like (nHDL) particles generated by incubating cells over-expressing ABCA1 with ATI-5261 increase the rate of specific ABCA1 dependent lipid efflux, with high affinity interactions with ABCA1. We also show that these nHDL particles interact with membrane micro-domains in a manner similar to nHDL apoA-I. These nHDL particles then interact with the ABCG1 transporter and are remodeled by plasma HDL-modulating enzymes. Finally, we show that these mature HDL-like particles are taken up by SR-BI for cholesterol delivery to liver cells. This ATI-5621-mediated process mimics apoA-I and may provide a means to prevent cholesterol accumulation in the artery wall. In this study, we propose an integrative physiology approach of HDL biogenesis with the synthetic peptide ATI-5261. These experiments provide new insights for potential therapeutic use of apolipoprotein mimetic peptides.
authors.affiliation: Cardiovascular Genetics Laboratory, Cardiology Division, McGill University Health Centre/Royal Victoria Hospital, Montréal, Québec H3A 1A1, Canada.
authors.forename: Anouar
authors.initials: A
authors.lastname: Hafiane
authors.affiliation: Lawrence Berkeley National Laboratory, Donner Laboratory, MS1-267 Berkeley, CA, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Bielicki
authors.affiliation: Artery Therapeutics, San Ramon, CA, USA.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Johansson
authors.affiliation: Cardiovascular Genetics Laboratory, Cardiology Division, McGill University Health Centre/Royal Victoria Hospital, Montréal, Québec H3A 1A1, Canada. Electronic address: jacques.genest@mcgill.ca.
authors.forename: Jacques
authors.initials: J
authors.lastname: Genest
keywords: ABCA1; ABCG1; Cholesterol efflux; HDL; Reverse cholesterol transport; SR-BI