Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL.
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.
Vaisar
Tomas
T
Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Pennathur
Subramaniam
S
Green
Pattie S
PS
Gharib
Sina A
SA
Hoofnagle
Andrew N
AN
Cheung
Marian C
MC
Byun
Jaeman
J
Vuletic
Simona
S
Kassim
Sean
S
Singh
Pragya
P
Chea
Helen
H
Knopp
Robert H
RH
Brunzell
John
J
Geary
Randolph
R
Chait
Alan
A
Zhao
Xue-Qiao
XQ
Elkon
Keith
K
Marcovina
Santica
S
Ridker
Paul
P
Oram
John F
JF
Heinecke
Jay W
JW
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
D008075:Lipoproteins, HDL; D010447:Peptide Hydrolases