Cited by 944Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthAtherosclerosis and Cardiovascular Diseases

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

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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.·2007·Journal of Clinical Investigation

DOI 10.1172/jci26206PMC PMC1804352

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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.

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Authors: Vaisar, T., Pennathur, S., Green, P. S., Gharib, S. A., Hoofnagle, A. N., Cheung, M. C., Byun, J., Vuletic, S., Kassim, S., Singh, P., Chea, H., Knopp, R. H., Brunzell, J., Geary, R., Chait, A., Zhao, X.-Q., Elkon, K., Marcovina, S., Ridker, P., Oram, J. F., & Heinecke, J. W.
Affiliations: University of Washington (US)
Wake Forest University (US)
Harvard University (US)
Corresponding author: Heinecke, Jay W.
ORCID: Pennathur, Subramaniam
Gharib, Sina A.
Hoofnagle, Andrew N.
Kassim, Sean
Singh, Pragya
Brunzell, John
Chait, Alan
Elkon, Keith
Marcovina, Santica
Ridker, Paul
Heinecke, Jay W.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2007-03-01
Volume: 117
Issue: 3
Pages: 746-756
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci26206
PMC: PMC1804352
OpenAlex: W2083315579
Cited by: 942
References: 70
Citations by year: 2026: 16 · 2025: 20 · 2024: 19 · 2023: 25 · 2022: 36 · 2021: 28 · 2020: 35 · 2019: 36 · 2018: 45 · 2017: 31 · 2016: 51 · 2015: 69 · 2014: 58 · 2013: 81 · 2012: 79
FWCI: 79.98
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: University of Washington (P30ES07033)
National Institutes of Health (P30ES07033, DK017047)
National Heart, Lung, and Blood Institute (HL086798, P01HL030086, HL-078527, K08HL074223, HL-57557, HL074223, R01HL086798, R01HL057557, R01HL078527)
National Institute of Diabetes and Digestive and Kidney Diseases (DK017047, DK 02456, P01DK002456, P30DK017047)
National Institute of Environmental Health Sciences (P30 ES-07033, P30ES007033)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Keywords: HDL cholesterol, HDL proteome, complement regulation, serpins, protease inhibition, anti-inflammatory activity, coronary artery disease, HDL3, apolipoprotein E, acute phase proteins, atherosclerosis, cardiovascular disease
MeSH terms: Amino Acid Sequence, Chromatography, Liquid, Complement Activation, Coronary Artery Disease, Humans, Inflammation, Lipoproteins, HDL, Microscopy, Electron, Scanning, Molecular Sequence Data, Peptide Hydrolases, Mass Spectrometry, Proteomics, Lipid Metabolism

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

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