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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Background
Proteomic Determinants of Variation in Cholesterol Efflux: Observations from the Dallas Heart Study
Gangwar, A., Deodhar, S., Saldanha, S., Melander, O., Abbasi, F., Pearce, R. W., Collier, T. S., McPhaul, M. J., Furtado, J. D., Sacks, F. M., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242115526 · Cited by 10
Identification of Plasma Free Fatty Acid Carrier Proteins in Mice
Tomoo, K., Zhang, Y., Mohallem, R., Aryal, U. K., Klauda, J. B., & Henderson, G. C. (2025) · The FASEB Journal · doi:10.1096/fj.202501328r · Cited by 9
“Interestingly, FFAs were found in lipoprotein fractions isolated by ultracentrifugation [8–11]; nevertheless, it should be noted that this method is not perfect for separating albumin and lipoprotein particles [12, 13], and therefore albumin-bound FFA might contaminate the lipoprotein fractions.”
High-density lipoproteins. Part 2. Impact of disease states on functionality
Gluba-Brzózka, A., Olszewski, R., Franczyk, B., Młynarska, E., Rysz-Górzyńska, M., Rysz, J., Surma, S., Sheth, S., Banach, M., & Toth, P. P. (2025) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2025.101073 · Cited by 12
“Among these proteins there is hemopexin, an iron-binding protein, and haptoglobin, which binds hemoglobin released from erythrocytes[81].”
High-density lipoprotein: a biomarker and therapeutic target in sepsis
Li, M., Barros-Pinkelnig, M., Arbous, M. S., Christoffersen, C., Rensen, P. C. N., & Kooijman, S. (2025) · Critical Care · doi:10.1186/s13054-025-05702-2 · Cited by 11
“In contrast to LDL, which is a relatively homogeneous population of particles with similar size, carrying a single copy of ApoB100 as the main apolipoprotein per particle, HDL comprises a heterogeneous population of particles with a wide range of sizes and (apolipo-) proteins [51].”
High-density lipoprotein (HDL) cholesterol: leveraging practice-based biobank cohorts to characterize clinical and genetic predictors of treatment outcome
Wilke, R. A. (2010) · The Pharmacogenomics Journal · doi:10.1038/tpj.2010.86 · Cited by 9
CETP Inhibition: Does the Future Look Promising?
Toth, P. P. (2011) · Current Cardiology Reports · doi:10.1007/s11886-011-0218-x · Cited by 9
Cytokines for the treatment of gastrointestinal cancers: clinical experience and new perspectives
Hernández-Alcoceba, R., Sangro, B., Berraondo, P., González‐Aseguinolaza, G., & Prìeto, J. (2013) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2013.793307 · Cited by 9
“The hydrophobic lipid core of HDLs is enveloped by proteins involved in lipid transport, but other proteins use the HDLs as vehicles to circulate to distant tissues (serpins, complement and acute phase proteins) [89].”
Background
Impact of genetic deletion of platform apolipoproteins on the size distribution of the murine lipoproteome
Gordon, S. M., Li, H., Zhu, X., Tso, P., Reardon, C. A., SHAH, A. S., Lu, L. J., & Davidson, W. S. (2016) · Journal of Proteomics · doi:10.1016/j.jprot.2016.06.035 · Cited by 9
What does HDL do? A new mechanism to slow atherogenesis – But a new problem in type 2 diabetes mellitus
Williams, K. J. (2012) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2012.06.023 · Cited by 9
Effect of an Isoenergetic Traditional Mediterranean Diet on the High-Density Lipoprotein Proteome in Men with the Metabolic Syndrome
Richard, C., Couture, P., Desroches, S., Nehmé, B., Bourassa, S., Droit, A., & Lamarche, B. (2014) · Lifestyle Genomics · doi:10.1159/000363137 · Cited by 9
Sphingomyelin regulation of plasma membrane asymmetry, efflux and reverse cholesterol transport
Gulshan, K., & Smith, J. D. (2014) · Clinical Lipidology · doi:10.2217/clp.14.28 · Cited by 9
Nitrated apolipoprotein A-I, a potential new cardiovascular marker, is markedly increased in low high-density lipoprotein cholesterol subjects
Bakillah, A. (2008) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2009.017 · Cited by 9
Effects of diet on genetic regulation of lipoprotein metabolism in baboons
Rainwater, D. L., VandeBerg, J. L., & Mahaney, M. C. (2010) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2010.08.079 · Cited by 9
High-Density Lipoproteins
Francis, G. A. (2015) · Elsevier eBooks · doi:10.1016/b978-0-444-63438-2.00015-8 · Cited by 12
Latest Insights Into High-Density Lipoprotein Functions
Noto, H. (2009) · The Endocrinologist · doi:10.1097/ten.0b013e3181a6a5ed · Cited by 9
Active antithrombin glycoforms are selectively physiosorbed on plasma extracellular vesiclesPreprint
Radeghieri, A., Alacqua, S., Zendrini, A., Previcini, V., Todaro, F., Martini, G., Ricotta, D., & Bergese, P. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.16.452649 · Cited by 9
High-density lipoproteins, Part 1. Epidemiology, antiatherogenic effects, and therapies designed to increase their serum levels
Franczyk, B., Młynarska, E., Rysz-Górzyńska, M., Gluba-Brzózka, A., Rysz, J., Sheth, S., Surma, S., Banach, M., & Toth, P. P. (2025) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2025.101068 · Cited by 10
“Other proteins include hemopexin, an iron-binding protein, and haptoglobin, which binds hemoglobin released from erythrocytes [121].”
Gelsolin: a new biomarker of disease activity in SLE patients associated with HDL-c
Parra, S., Heras, M., Herrero, P., Amigó, N., Garcés, E., Girona, J., Correig, X., Canela-Canela, N., & Castro, A. (2019) · Lara D. Veeken · doi:10.1093/rheumatology/kez293 · Cited by 8
“Novel proteins associated with HDL are associated with diverse biological functions beyond lipid metabolism, such as the acute phase response and the activation of the immune and the complement system [12][13] [14][15].”
Association of ApoE and HDL.C with cardiovascular and cerebrovascular disease: potential benefits of LDL-apheresis therapy
Moriarty, P. M. (2009) · Clinical Lipidology · doi:10.2217/clp.09.21 · Cited by 9
Lipoprotein Metabolism and the Treatment of Lipid Disorders
Freeman, M. W., & Walford, G. A. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-18907-1.00041-x · Cited by 10
Connective tissue and inflammation
Jakab, L. (2014) · Orvosi Hetilap · doi:10.1556/oh.2014.29848 · Cited by 8
Functionality of HDL particles: Heterogeneity and relationships to cardiovascular disease
Camont, L., Chapman, J., & Kontush, A. (2011) · Archives of Cardiovascular Diseases Supplements · doi:10.1016/s1878-6480(11)70784-4 · Cited by 8
The Deleterious Influence of Tenofovir-Based Therapies on the Progression of Atherosclerosis in HIV-Infected Patients
Aragonès, G., Pardo-Reche, P., Fernández-Sénder, L., Rull, A., Beltrán‐Debón, R., Rodríguez‐Gallego, E., Camps, J., Joven, J., & Alonso‐Villaverde, C. (2012) · Mediators of Inflammation · doi:10.1155/2012/372305 · Cited by 8
“Our results indicated that HDL particles modulate not only reverse cholesterol transport but also the inflammatory response [14, 15].”
Result
Analysis of low‐density lipoprotein‐associated proteins using the method of digitized native protein mapping
Jin, Y., Chen, J., Wang, A., Zhang, J., Chen, S., Manabe, T., & Tan, W. (2016) · Electrophoresis · doi:10.1002/elps.201600100 · Cited by 8
ApoA‐I mutations, L202P and K131del, in HDL from heterozygotes with low HDL‐C
Ljunggren, S., Levels, J. H. M., Turkina, M. V., Sundberg, S., Bochem, A. E., Hovingh, K., Holleboom, A. G., Lindahl, M. G., Kuivenhoven, J. A., & Karlsson, H. (2013) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.201300014 · Cited by 8
Plasma proteome correlates of lipid and lipoprotein: biomarkers of metabolic diversity and inflammation in children of rural Nepal
Lee, S. E., Schulze, K. J., Stewart, C. P., Cole, R. N., Wu, L. S.-F., Eroglu, A., Yager, J. D., Groopman, J. D., Christian, P. S., & West, K. P. (2018) · Journal of Lipid Research · doi:10.1194/jlr.p088542 · Cited by 8
“4 55743122 (7, 80, 82, 84, 85, 87, 88, 90) CD99 molecule (CD99) 444 0.”
Influential
High-density lipoprotein: what is the best way to measure its antiatherogenic potential?
Remaley, A. T., & Warnick, G. R. (2008) · Expert Opinion on Medical Diagnostics · doi:10.1517/17530059.2.7.773 · Cited by 8
Associations of HDL subclasses and lipid content with complement proteins over the menopause transition: The SWAN HDL ancillary study
Khoudary, S. R. E., Chen, X., McConnell, D. S., Brooks, M. M., Billheimer, J. T., & Orchard, T. J. (2022) · Journal of clinical lipidology · doi:10.1016/j.jacl.2022.07.015 · Cited by 7
Utility of high density lipoprotein particle concentration in predicting future major adverse cardiovascular events among patients undergoing angiography
May, H. T., Anderson, J. L., Winegar, D. A., Rollo, J. S., Connelly, M. A., Otvos, J. D., & Muhlestein, J. B. (2016) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2016.09.004 · Cited by 7
Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids
Barnhart, S., Shimizu‐Albergine, M., Kedar, E., Kothari, V. M., Shao, B., Krueger, M. A., Hsu, C.-C., Tang, J., Kanter, J. E., Kramer, F., et al. (2024) · Journal of Lipid Research · doi:10.1016/j.jlr.2024.100730 · Cited by 7
Self-citation
Plasma levels of antibodies against oxidized LDL are inherited but not associated with HDL-cholesterol level in families with early coronary heart disease
Paavola, T., Kangas‐Kontio, T., Salonurmi, T., Kuusisto, S. M., Huusko, T. J., Savolainen, M. J., & Kakko, S. (2012) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2012.06.056 · Cited by 7
Synthesis, Hirshfeld surface analysis, spectral investigations, DFT calculations, ADME studies and molecular docking of Hexahydropyrimidines derivative against dimeric Apolipoprotein A-IV
Saraswathi, K. T., Suresh, M., & Pandurangan, A. (2022) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2022.132447 · Cited by 7
Effect of Anti-ApoA-I Antibody-Coating of Stents on Neointima Formation in a Rabbit Balloon-Injury Model
Strang, A. C., Knetsch, M. L. W., Koole, L. H., de Winter, R. J., van der Wal, A. C., de Vries, C. J. M., Tak, P. P., Bisoendial, R. J., Stroes, E. S. G., & Rotmans, J. I. (2015) · PLoS ONE · doi:10.1371/journal.pone.0122836 · Cited by 7
“[38,39] Mechanistically, HDL has been shown to serve as a carrier of a wide array of proteins affecting the innate immune system and proteolytic cascades.[40] In line, systemic infusion of HDL has been shown to reduce vessel wall inflammation.”
Background
Protein changes in non-LDL-lipoproteins in familial hypercholesterolemia: implications in cardiovascular disease manifestation and outcome
Badimón, L., Padró, T., & Cubedo, J. (2017) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000441 · Cited by 7
“ticles contain proteins involved not only in lipid metabolism, but also in complement regulation, acute phase response and proteinase inhibition, among others [24].”
Background
Possible Insulinotropic Action of Apolipoprotein A–I Through the ABCA1/Cdc42/cAMP/PKA Pathway in MIN6 Cells
Matsumura, K., Tamasawa, N., & Daimon, M. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00645 · Cited by 7
“Besides cholesterol efflux, HDL/ApoA-I has many other physiological functions, including anti-oxidative, anti-inflammatory, antiapoptotic, and anti-thrombotic roles (9, 10).”
Background
Lipoproteins: from A to B and maybe C-III
Wierzbicki, A. S. (2008) · International Journal of Clinical Practice · doi:10.1111/j.1742-1241.2008.01718.x · Cited by 7
High-density lipoprotein is superior to B-type natriuretic peptide as a marker of systolic dysfunction in an elderly general population
Kerola, T. V., Nieminen, T. V. M., Hartikainen, S. A., Sulkava, R. O., Vuolteenaho, O. J., & Kettunen, R. (2009) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.3109/00365510903359237 · Cited by 7
The Complexity of High-Density Lipoproteins
Fogelman, A. M. (2010) · Circulation · doi:10.1161/circulationaha.110.984120 · Cited by 7
Does HDL (High-Density Lipoprotein) Play a Causal Role in Host Defenses Against Infection?
Heinecke, J. W. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.119.313651 · Cited by 7
Self-citation

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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