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  2. ABCA1 Agonist Mimetic Peptide CS-6253 Induces Microparticles Release From Different Cell Types by ABCA1-Efflux-Dependent Mechanism

ABCA1 Agonist Mimetic Peptide CS-6253 Induces Microparticles Release From Different Cell Types by ABCA1-Efflux-Dependent Mechanism

  • Can J Cardiol. 2019 Jun;35(6):770-781. doi: 10.1016/j.cjca.2019.02.018.
Anouar Hafiane 1 Jan O Johansson 2 Jacques Genest 3
Affiliations

Affiliations

  • 1 Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, Montreal, Québec, Canada. Electronic address: anouar.hafiane@mail.mcgill.ca.
  • 2 Department of Medicine, Artery Therapeutics, San Ramon, California, USA.
  • 3 Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Québec, Canada.
Abstract

Background: Small Peptides based on the C-terminal domain of apo E have recently been proposed as ATP-binding cassette transporter A1 (ABCA1) agonist with therapeutic potential. Previous work has shown that a novel synthetic peptide, CS-6253, acts synergistically with apolipoprotein A-I or alone to generate high-density lipoprotein (HDL) particles; we have also shown that cells can release microparticles (50-350 nm in apparent diameter) in an ABCA1- and apolipoprotein A-I-dependent manner. The purpose of this study was to explore the ability of a novel synthetic peptide CS-6253 to induce microparticle release from various cell lines in the process of HDL biogenesis.

Methods: The effects of CS-6253 on microparticle formation through the ABCA1 transporter were examined in vitro using cell-based systems and pharmacologic manipulations.

Results: In cell-based systems combined with fast performance liquid chromatography and nano-sight-tracking analysis, we show that ABCA1 and CS-6253 mediate and increase the production of microparticles containing Cholesterol. CS-6253 in baby hamster kidney cells not expressing ABCA1 (baby hamster kidney mock cells) did not alter Cholesterol removal across the plasma membrane in the absence of ABCA1 expression even at high concentrations. We report that CS-6253 is not cytotoxic.

Conclusions: The present study shows that CS-6253 generates Cholesterol containing microparticles with size heterogeneity (100-350 nm) in an ABCA1-dependent manner. We show that microparticles contribute to cell Cholesterol efflux from monocyte-macrophage cells. At high doses, CS-6253 is not able to extract Cholesterol from cells not expressing ABCA1, indicating that CS-6253 requires ABCA1 cooperation for Cholesterol mobilization. We conclude that CS-6253 is an ABCA1 agonist peptide that promotes cellular Cholesterol efflux through HDL biogenesis and microparticle formation.

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