Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL

• Published in: The Journal of clinical investigation Vol. 117; no. 3; pp. 746 - 756
• Main Authors: Vaisar, Tomas, Pennathur, Subramaniam, Green, Pattie S., Gharib, Sina A., Hoofnagle, Andrew N., Cheung, Marian C., Byun, Jaeman, Vuletic, Simona, Kassim, Sean, Singh, Pragya, Chea, Helen, Knopp, Robert H., Brunzell, John, Geary, Randolph, Chait, Alan, Zhao, Xue-Qiao, Elkon, Keith, Marcovina, Santica, Ridker, Paul, Oram, John F., Heinecke, Jay W.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2007
• Subjects: Amino Acid Sequence; Anti-inflammatory drugs; Apolipoproteins; Atherosclerosis; Biomedical research; Cardiovascular disease; Cholesterol; Chromatography; Chromatography, Liquid; Complement Activation; Coronary Artery Disease - enzymology; Coronary Artery Disease - immunology; Coronary vessels; Health aspects; High density lipoprotein; Humans; Inflammation - metabolism; Lipid Metabolism; Lipoproteins; Lipoproteins, HDL - blood; Lipoproteins, HDL - isolation & purification; Lipoproteins, HDL - metabolism; Mass Spectrometry; Microscopy, Electron, Scanning; Molecular biology; Molecular Sequence Data; Mortality; Oxidation; Peptide Hydrolases - metabolism; Peptides; Protease inhibitors; Proteins; Proteomics; Scientific imaging; Vein & artery diseases; United States > US
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI26206

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.