title: Pegylation of high-density lipoprotein decreases plasma clearance and enhances antiatherogenic activity.
abstract: BACKGROUND
  Infusions of apolipoprotein AI (apoAI), mimetic peptides, or high-density lipoprotein (HDL) remain a promising approach for the treatment of atherosclerotic coronary disease. However, rapid clearance leads to a requirement for repeated administration of large amounts of material and limits effective plasma concentrations.
  
  
  OBJECTIVE
  Because pegylation of purified proteins is commonly used as a method to increase their half-life in the circulation, we determined whether pegylation of apoAI or HDL would increase its plasma half-life and in turn its antiatherogenic potential.
  
  
  RESULTS
  Initial pegylation attempts using lipid-poor apoAI showed a marked tendency to form multi-pegylated (PEG) species with reduced ability to promote cholesterol efflux from macrophage foam cells. However, pegylation of human holo-HDL or reconstituted phospholipid/apoAI particles (rHDL) led to selective N-terminal monopegylation of apoAI with full preservation of cholesterol efflux activity. The plasma clearance of PEG-rHDL was estimated after injection into hypercholesterolemic Apoe-/- mice; the half-life of pegylated PEG-apoAI after injection of PEG-rHDL was increased ≈7-fold compared with apoAI in nonpegylated rHDL. In comparison with nonpegylated rHDL, infusion of PEG-rHDL (40 mg/kg) into hypercholesterolemic Apoe-/- mice led to more pronounced suppression of bone marrow myeloid progenitor cell proliferation and monocytosis, as well as reduced atherosclerosis and a stable plaque phenotype.
  
  
  CONCLUSIONS
  We describe a novel method for effective monopegylation of apoAI in HDL particles, in which lipid binding seems to protect against pegylation of key functional residues. Pegylation of apoAI in rHDL markedly increases its plasma half-life and enhances antiatherogenic properties in vivo.
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Funt
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Darren
authors.initials: D
authors.lastname: Gorman
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000517:prevention & control*; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control*; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D006207:Half-Life; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000473:pathology / Q000517:prevention & control; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; D011092:Polyethylene Glycols; D002784:Cholesterol
keywords: HDL; apoAI; atherosclerosis; cholesterol; hematopoiesis