title: Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL.
abstract: HDL lowers the risk for atherosclerotic cardiovascular disease by promoting cholesterol efflux from macrophage foam cells. However, other antiatherosclerotic properties of HDL are poorly understood. To test the hypothesis that the lipoprotein carries proteins that might have novel cardioprotective activities, we used shotgun proteomics to investigate the composition of HDL isolated from healthy subjects and subjects with coronary artery disease (CAD). Unexpectedly, our analytical strategy identified multiple complement-regulatory proteins and a diverse array of distinct serpins with serine-type endopeptidase inhibitor activity. Many acute-phase response proteins were also detected, supporting the proposal that HDL is of central importance in inflammation. Mass spectrometry and biochemical analyses demonstrated that HDL3 from subjects with CAD was selectively enriched in apoE, raising the possibility that HDL carries a unique cargo of proteins in humans with clinically significant cardiovascular disease. Collectively, our observations suggest that HDL plays previously unsuspected roles in regulating the complement system and protecting tissue from proteolysis and that the protein cargo of HDL contributes to its antiinflammatory and antiatherogenic properties.
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Vaisar
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.forename: Pattie S
authors.initials: PS
authors.lastname: Green
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Hoofnagle
authors.forename: Marian C
authors.initials: MC
authors.lastname: Cheung
authors.forename: Jaeman
authors.initials: J
authors.lastname: Byun
authors.forename: Simona
authors.initials: S
authors.lastname: Vuletic
authors.forename: Sean
authors.initials: S
authors.lastname: Kassim
authors.forename: Pragya
authors.initials: P
authors.lastname: Singh
authors.forename: Helen
authors.initials: H
authors.lastname: Chea
authors.forename: Robert H
authors.initials: RH
authors.lastname: Knopp
authors.forename: John
authors.initials: J
authors.lastname: Brunzell
authors.forename: Randolph
authors.initials: R
authors.lastname: Geary
authors.forename: Alan
authors.initials: A
authors.lastname: Chait
authors.forename: Xue-Qiao
authors.initials: XQ
authors.lastname: Zhao
authors.forename: Keith
authors.initials: K
authors.lastname: Elkon
authors.forename: Santica
authors.initials: S
authors.lastname: Marcovina
authors.forename: Paul
authors.initials: P
authors.lastname: Ridker
authors.forename: John F
authors.initials: JF
authors.lastname: Oram
authors.forename: Jay W
authors.initials: JW
authors.lastname: Heinecke
mesh_terms: D000595:Amino Acid Sequence; D002853:Chromatography, Liquid; D003167:Complement Activation; D003324:Coronary Artery Disease / Q000201:enzymology / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism*; D013058:Mass Spectrometry; D008855:Microscopy, Electron, Scanning; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000378:metabolism*; D040901:Proteomics
chemical_list: D008075:Lipoproteins, HDL; D010447:Peptide Hydrolases