title: HDL from apoA1 transgenic mice expressing the 4WF isoform is resistant to oxidative loss of function.
abstract: HDL functions are impaired by myeloperoxidase (MPO), which selectively targets and oxidizes human apoA1. We previously found that the 4WF isoform of human apoA1, in which the four tryptophan residues are substituted with phenylalanine, is resistant to MPO-mediated loss of function. The purpose of this study was to generate 4WF apoA1 transgenic mice and compare functional properties of the 4WF and wild-type human apoA1 isoforms in vivo. Male mice had significantly higher plasma apoA1 levels than females for both isoforms of human apoA1, attributed to different production rates. With matched plasma apoA1 levels, 4WF transgenics had a trend for slightly less HDL-cholesterol versus human apoA1 transgenics. While 4WF transgenics had 31% less reverse cholesterol transport (RCT) to the plasma compartment, equivalent RCT to the liver and feces was observed. Plasma from both strains had similar ability to accept cholesterol and facilitate ex vivo cholesterol efflux from macrophages. Furthermore, we observed that 4WF transgenic HDL was partially (∼50%) protected from MPO-mediated loss of function while human apoA1 transgenic HDL lost all ABCA1-dependent cholesterol acceptor activity. In conclusion, the structure and function of HDL from 4WF transgenic mice was not different than HDL derived from human apoA1 transgenic mice.
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Stela Z
authors.initials: SZ
authors.lastname: Berisha
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Greg
authors.initials: G
authors.lastname: Brubaker
authors.affiliation: Department of Gastroenterology and Hepatology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Takhar
authors.initials: T
authors.lastname: Kasumov
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Kimberly T
authors.initials: KT
authors.lastname: Hung
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: DiBello
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Research Core Services, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Research Core Services, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Pollard
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195. Electronic address: smithj4@ccf.org.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D009195:Peroxidase; D020033:Protein Isoforms; C577836:ABCA1 protein, human; C577833:Abca1 protein, mouse; C505693:APOA1 protein, human
keywords: ATP binding cassette transporter A1; apolipoprotein A1; cholesterol efflux; dysfunctional high density lipoprotein; myeloperoxidase; reverse cholesterol transport