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Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL
Open accessAbstract
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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“Unlike HDL from healthy subjects, HDL from patients with CHD, kidney disease or diabetes mellitus have no protective vascular effects or may even cause paradoxical harmful effects [55, 56, 61, 70, 71, 75, 76].”
From HDL cholesterol: reappraisal of its clinical relevance (2017) · cites this paper as [56]
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“15,16 For example, it has been shown that CFH levels could be greatly increased in large HDL and may explain the ability of HDL to prevent the organization of complement membrane attack complex and to suppress in fl ammation.”
A two-step homogeneous assay for apolipoprotein E-containing high-density lipoprotein-cholesterol
Takahashi, Y., Ito, Y., Sakurai, T., Wada, N., Nagasaka, A., Fujikawa, M., Chiba, H., & Hui, S. (2018) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/0004563218795212 · Cited by 3
“HDL contains approximately 100 protein species, including apolipoprotein A-I, A-II, Cs and E.(8) As shown in apolipoprotein E (apoE)-knockout mice, apoE is associated with antiatherogenicity.”
The way of self-defence of the organism: inflammation
Jakab, L. (2013) · Orvosi Hetilap · doi:10.1556/oh.2013.29670 · Cited by 6
Immunoprecipitation of apolipoprotein B-containing lipoproteins for isolation of HDL particles
Contois, J. H., Albert, A. L., & Nguyen, R.-A. (2014) · Clinica Chimica Acta · doi:10.1016/j.cca.2014.06.017 · Cited by 3
Changing paradigm in HDL metabolism and cellular effects
van Wijk, D. F., Stroes, E. S. G., & Monajemi, H. (2009) · Clinical Lipidology · doi:10.2217/17584299.4.1.17 · Cited by 3
Effects of pitavastatin on HDL metabolism
Kishida, K., Funahashi, T., & Shimomura, I. (2013) · Clinical Lipidology · doi:10.2217/clp.12.87 · Cited by 3
Antwi-Baffour, S. S., Kyeremeh, R., Adjei, J. K., Aryeh, C., & Kpentey, G. (2016) · Autoimmunity Highlights · doi:10.1007/s13317-016-0078-x · Cited by 4
Identifying new Risk Markers and Potential Targets: The Value of the Proteome
Kontush, A. (2016) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-016-6656-3 · Cited by 3
High-Density Lipoprotein Metabolism
Brewer, H. B. (2009) · Clinical Lipidology · doi:10.1016/b978-141605469-6.50008-1 · Cited by 3
High-Density Lipoprotein Metabolism
Brewer, H. B. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-28786-9.00004-9 · Cited by 3
Segrest, J. P. (2015) · Springer eBooks · doi:10.1007/978-3-319-17350-4_1 · Cited by 3
Darabi, M., Zakiev, E., & Kontush, A. (2020) · Contemporary cardiology · doi:10.1007/978-3-030-56514-5_18 · Cited by 3
Nilsson, P., Viljoen, A., & Wierzbicki, A. (2010) · doi:10.1002/9781444324808.ch40 · Cited by 1
High-Density Lipoprotein and Residual Cardiovascular Risk
Genest, J. J. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.05.087 · Cited by 3
“Furthermore, the protein composition of HDL, once thought to be relatively simple, has shown remarkable biological diversity (20); there are nearly 80 proteins identified in the HDL fraction, and the HDL proteome is altered in inflammatory states, such as acute coronary syndromes (21).”
BackgroundRodríguez‐Carrio, J., Alpéri, M., López, P., Pérez-Álvarez, Á. I., Robinson, G., Alonso-Castro, S., Amigó, N., Atzeni, F., & Suárez, A. (2022) · medRxiv · doi:10.1101/2022.08.12.22278696 · Cited by 3
Song, S., Wu, H., Liu, Y., Lan, D., Jiao, B., Wan, S., Guo, Y., Zhou, D., Ding, Y., Ji, X., et al. (2023) · Chinese Medical Journal · doi:10.1097/cm9.0000000000002572 · Cited by 2
“Recent proteomic analyses revealed more than 50 unique bona fide protein components in HDL.[31-33] Moreover, many of these protein components have reportedly no known role in inter- or intracellular lipid mobilization, rather involved in diverse cellular processes like innate immunity, protease inhibition, platelet fu…”
BackgroundInfluentialMeng, L., Jin, W., Ye, K., Yan, Y., Ding, C., & LI, K. S. (2026) · Microchemical Journal · doi:10.1016/j.microc.2026.117098 · Cited by 2
High density lipoproteins and kidney function: the friend turned foe?
Badimón, L., Vilahur, G., & Cubedo, J. (2016) · Journal of Thoracic Disease · doi:10.21037/jtd.2016.11.66 · Cited by 2
Low plasma apolipoprotein E-rich high-density lipoprotein levels in patients with metabolic syndrome
Shinohata, R., Shiga, Y., Miura, S.-I., Hirohata, S., Shibakura, M., Ueno-Iio, T., Watanabe, S., Arao, Y., & Usui, S. (2020) · Clinica Chimica Acta · doi:10.1016/j.cca.2020.08.020 · Cited by 2
Maravi, J. S. M., Leszczynski, E. C., Schwartz, C. S., Dev, P. K., Barber, J. L., Reasons, R. J., Pearce, R. W., McPhaul, M. J., Konrad, R. J., Robbins, J., et al. (2024) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.117587 · Cited by 2
Wen, J., & Zhang, Z. (2024) · BMC Infectious Diseases · doi:10.1186/s12879-024-10125-5 · Cited by 2
Evaluación de la heterogeneidad y función de HDL por el laboratorio
Movva, R., & Rader, D. J. (2009) · Redalyc (Universidad Autónoma del Estado de México) · Cited by 2
The neutral protease chymase degrades apolipoprotein E from high-density lipoproteins
Lee‐Rueckert, M., von Eckardstein, A., & Kovanen, P. T. (2008) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2008.072 · Cited by 2
“As HDL particles in human atherosclerotic lesions are enriched in apoE (15), we conclude that extracellular proteolysis of apoE-containing HDL is a novel inhibitory principle that may interfere with the initiation of reverse cholesterol transport in the atherosclerotic arterial intima.”
BackgroundHigh-Density Lipoprotein: Is the Good Cholesterol Turning Bad?
Inankur, A., Nicholls, S. J., & Jahangiri, A. (2010) · Current Cardiovascular Risk Reports · doi:10.1007/s12170-010-0143-3 · Cited by 2
“In addition to its protective protein components (apoA-I, apoJ, PON-1, and PON-3), HDL also contains numerous other proteins such as the complement family, endopeptidase inhibitors, and pro-inflammatory molecules (SAA) [53].”
BackgroundZhao, X.-Q., & Kerwin, W. S. (2012) · Clinical Lipidology · doi:10.2217/clp.12.33 · Cited by 2
Self-citationDuong, M., & Nicholls, S. J. (2009) · Expert Opinion on Drug Discovery · doi:10.1517/17460440903008510 · Cited by 2
“Using a shotgun proteomic approach, it was recently reported that > 40 different proteins regulating a range of inflammatory and thrombotic cascades, in addition to roles in cholesterol homeostasis, were found within the plasma density fraction containing HDL [44].”
Background
Metadata
- 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
- Venue
- Journal of Clinical Investigation
- Published
- 2007-03-01
- Volume
- 117
- Issue
- 3
- Pages
- 746-756
- ISSN
- 0021-9738 (ISSN-L)
- 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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