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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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“…2018 | Volume 8 | Article 989 linked to particular activities, including complement activation, the innate immune response, oxidative stress and regulation of proteinase activity, through which a number of pathological processes could be influenced (Vaisar et al., 2007; Davidson et al., 2009).”
BackgroundChristoffersen, C., Ahnström, J., Axler, O., Christensen, E., Dahlbäck, B., & Nielsen, L. B. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800695200 · Cited by 75
HDL-cholesterol in coronary artery disease risk: Function or structure?
Pérez-Méndez, O. A., González‐Pacheco, H., Martínez‐Sánchez, C., & Franco, M. (2013) · Clinica Chimica Acta · doi:10.1016/j.cca.2013.12.001 · Cited by 80
“During inflammation, HDL cargo is modified, and HDL not only lose their protective capacity [55–62,72,73], but they become proinflammatory; HDL become particularly enriched with serum amyloid A (SAA) [72] and complement component 3 (C3) during psoriasis [74], chronic kidney disease [75], rheumatoid arthritis [76], as…”
BackgroundMoghimi, S. M., Simberg, D., Papini, E., & Farhangrazi, Z. S. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.04.012 · Cited by 75
“, HDL3) are enriched with many complement proteins, and regulators to include C3, C4a, C4b, C9, vitronectin, and clusterin (apolipoprotein J) [81], which may be picked on proteomic analysis, again leading to incorrect interpretation.”
BackgroundHarnessing a Physiologic Mechanism for siRNA Delivery With Mimetic Lipoprotein Particles
Nakayama, T., Butler, J. S., Sehgal, A., Severgnini, M., Racie, T., Sharman, J., Ding, F., Shulga‐Morskaya, S., Brodsky, J., Tchangov, L., et al. (2012) · Molecular Therapy · doi:10.1038/mt.2012.33 · Cited by 75
Complement in age-related macular degeneration: a focus on function
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“Proteomics-based approaches have identified elevated high density lipoprotein (HDL)-apoE as being associated with coronary disease (7).”
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Diabetes Impairs Cellular Cholesterol Efflux From ABCA1 to Small HDL Particles
He, Y., Ronsein, G. E., Tang, C., Jarvik, G. P., Davidson, W. S., Kothari, V. M., Song, H. D., Segrest, J. P., Bornfeldt, K., & Heinecke, J. W. (2020) · Circulation Research · doi:10.1161/circresaha.120.317178 · Cited by 74
Self-citationIborra, R. T., Ribeiro, I. C. D., Neves, M. Q. T. S., Charf, A. M., Lottenberg, S. A., Negrão, C. E., Nakandakare, E. R., & Passarelli, M. (2008) · Scandinavian Journal of Medicine and Science in Sports · doi:10.1111/j.1600-0838.2007.00748.x · Cited by 70
Type 2 diabetes is associated with loss of HDL endothelium protective functions
Vaisar, T., Couzens, E., Hwang, A., Russell, M., Barlow, C. E., DeFina, L. F., Hoofnagle, A. N., & Kim, F. (2018) · PLoS ONE · doi:10.1371/journal.pone.0192616 · Cited by 75
Self-citationLocalized-Statistical Quantification of Human Serum Proteome Associated with Type 2 Diabetes
Li, R.-X., Chen, H.-B., Tu, K., Zhao, S.-L., Zhou, H., Li, S., Dai, J., Li, Q., Nie, S., Li, Y., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003224 · Cited by 72
“The label-free quantitation based on peptide-spectral counts offers a high-coverage identification of proteins, and then gives a comprehensive and rapid comparison to the differential proteins, especially to the plasma proteins [48].”
BackgroundLu, J., Zhang, S., Liu, L., Pang, X., Ma, C., Jiang, S., & Lv, J. (2018) · Food Chemistry · doi:10.1016/j.foodchem.2018.04.065 · Cited by 72
Navab, M., Reddy, S. T., Lenten, B. J. V., Buga, G. M., Hough, G., Wagner, A. C., & Fogelman, A. M. (2012) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.300282 · Cited by 72
“The levels of hemoglobin (a potent oxidant when freed from red blood cells) and haptoglobin (an acute phase reactant) that were associated with HDL in CAD patients significantly predicted the inflammatory properties and function of their HDL.76 HDL from patients with another chronic inflammatory condition (rheumatoid…”
ResultKhoudary, S. R. E., Wang, L., Brooks, M. M., Thurston, R. C., Derby, C. A., & Matthews, K. A. (2016) · Journal of clinical lipidology · doi:10.1016/j.jacl.2016.04.008 · Cited by 74
“One protein component that appears to be involved in the loss of anti-oxidative and anti-inflammatory activities of HDL is complement C3 protein, which was found to be enriched in HDL3 among CAD subjects (20).”
BackgroundApolipoprotein mimetic peptides: Mechanisms of action as anti-atherogenic agents
Osei-Hwedieh, D. O., Amar, M. J., Sviridov, D., & Remaley, A. T. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.12.003 · Cited by 71
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“Earlier studies have identified approximately 50 distinct proteins associated with the HDL fraction, using 2D electrophoresis and mass spectrometry approaches [19,25–29].”
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“High density lipoprotein may also have clinically important immunomodulatory and innate immune functions (4, 9, 10).”
BackgroundBerrougui, H., Loued, S., & Khalil, A. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.01.019 · Cited by 71
“Paraoxonase 1 (PON1) is one of the 8 most abundant HDL-associated proteins and may have atheroprotective properties [9].”
BackgroundA new era for quantifying HDL and cardiovascular risk?
Heinecke, J. W. (2012) · Nature Medicine · doi:10.1038/nm.2930 · Cited by 74
Self-citationVaisar, T., Kanter, J. E., Wimberger, J., Irwin, A. D., Gauthier, J., Wolfson, E. A., Bahnam, V., Wu, I., Shah, H., Keenan, H. A., et al. (2019) · Diabetes Care · doi:10.2337/dc19-0772 · Cited by 69
“In addition, the protein composition of HDL is altered with inflammatory disease, suggesting that protein composition may be a marker for, and perhaps a mediator of, vascular dysfunction (18).”
BackgroundSelf-citationGordon, S. M., & Remaley, A. T. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.11.015 · Cited by 72
“, who initially noted the presence of numerous protease inhibitors on HDL (23).”
BackgroundFrancis, G. A. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.08.009 · Cited by 69
Gerszten, R. E., Asnani, A. H., & Carr, S. A. (2011) · Circulation Research · doi:10.1161/circresaha.110.225003 · Cited by 71
Proteomics of Lipoprotein(a) identifies a protein complement associated with response to wounding
von Zychlinski, A., Kleffmann, T., Williams, M. J. A., & McCormick, S. P. A. (2011) · Journal of Proteomics · doi:10.1016/j.jprot.2011.07.008 · Cited by 69
Al‐Jarallah, A., & Trigatti, B. L. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.08.006 · Cited by 69
“proteins and enzymes other than those involved in lipid metabolism are also carried by HDL including proteins involved in complement regulation, acute phase responses and protease inhibition [15] (reviewed in [3–6,16,17]).”
BackgroundWang, Y., Ghoshal, S., Ward, M. R., de Villiers, W. J. S., Woodward, J. G., & Eckhardt, E. R. M. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008442 · Cited by 68
“Interestingly, lipoproteins with structural similarity to chylomicrons, HDL, bind many different proteins and peptides [15,16], and dietary antigens, such as OVA, peanut albumins, and milk caseins, have emulsifying properties [17–20], which suggests that protein antigens may also have affinity for chylomicrons.”
Red-fleshed sweet orange juice improves the risk factors for metabolic syndrome
da Silveira, J. Q., Dourado, G. K. Z. S., & Cesar, T. B. (2015) · International Journal of Food Sciences and Nutrition · doi:10.3109/09637486.2015.1093610 · Cited by 69
“Additionally, apolipoprotein B concentration was not changed, but apolipoprotein A1 decreased in normalweight individuals following the decrease of the HDL-C, since apo A1 is the main protein component of this particle (Vaisar et al., 2007).”
BackgroundHDL-replacement therapy: mechanism of action, types of agents and potential clinical indications
Remaley, A. T., Amar, M. J., & Sviridov, D. (2008) · Expert Review of Cardiovascular Therapy · doi:10.1586/14779072.6.9.1203 · Cited by 69
The effects of apolipoprotein B depletion on HDL subspecies composition and function
Davidson, W. S., Heink, A., Sexmith, H., Melchior, J., Gordon, S. M., Kuklenyik, Z., Woollett, L. A., Barr, J. R., Jones, J. I., Toth, C. A., et al. (2016) · Journal of Lipid Research · doi:10.1194/jlr.m066613 · Cited by 72
Should low high-density lipoprotein cholesterol (HDL-C) be treated?
Toth, P. P., Barylski, M., Nikolić, D., Rizzo, M., Montalto, G., & Banach, M. (2013) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2013.11.002 · Cited by 67
The Therapeutic Role of Niacin in Dyslipidemia Management
Boden, W. E., Sidhu, M. S., & Toth, P. P. (2013) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/1074248413514481 · Cited by 69
Unravelling HDL—Looking beyond the Cholesterol Surface to the Quality Within
Kajani, S., Curley, S., & McGillicuddy, F. C. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071971 · Cited by 70
“In addition, numerous complement proteins, serpin proteins, and acute-phase proteins were identified on the particles, many of which were enriched on HDL3 from patients with CAD [165].”
BackgroundHDL particle subpopulations: Focus on biological function
Rached, F. H., Chapman, M. J., & Kontush, A. (2015) · BioFactors · doi:10.1002/biof.1202 · Cited by 73
“Recent proteomic studies have typically identified more than 80 distinct proteins associated with HDL isolated either by ultracentrifugation or immunoaffinity chromatography [24,25].”
BackgroundProteomics Investigations of HDL: Challenges and Promise
Vaisar, T. (2012) · Current Vascular Pharmacology · doi:10.2174/157016112800812755 · Cited by 69
“[62–66] To characterize HDL proteome globally we employed two-stage ultracentrifugation to isolate HDL3, the dense sub-fraction of HDL, from plasma of seven apparently healthy subjects and used shotgun proteomics and two-dimensional LC-MS/MS with minimal sample manipulation to characterize HDL proteome.[56] After appl…”
BackgroundMethodInfluentialSelf-citationO'Reilly, M. E., Dillon, E., Guo, W., Finucane, O. M., McMorrow, A. M., Murphy, A. M., Lyons, C. L., Jones, D., Ryan, M., Gibney, M. J., et al. (2016) · Circulation · doi:10.1161/circulationaha.115.020278 · Cited by 67
“The HDL proteome is enriched with proinflammatory proteins in CVD.(10,12) Little, however, is known about the impact of obe-”
BackgroundInfluentialDysfunctional high-density lipoprotein
Feng, H., & Li, X. (2009) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0b013e32832922fc · Cited by 65
Coincubation of PON1, APO A1, and LCAT increases the time HDL is able to prevent LDL oxidation
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“Much more research into the HDL antioxidant system needs to be done to dissect the exact mechanism(s) at work, to show how the system operates in vivo and whether any other of the many HDL associated proteins (21) contribute to this activity.”
BackgroundIdentification of Fibrin Clot-Bound Plasma Proteins
Talens, S., Leebeek, F. W. G., Demmers, J., & Rijken, D. C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041966 · Cited by 64
“These findings are in line with the detection of fibrinogen in purified HDL preparations [29,36,37].”
ResultSimonsen, J. B. (2016) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2016.05.009 · Cited by 64
HDL particle number measured on the Vantera®, the first clinical NMR analyzer
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Overexpression of Apolipoprotein F Reduces HDL Cholesterol Levels In Vivo
Lagor, W. R., Brown, R., Toh, S.-A. E. S., Millar, J. S., Fuki, I. V., de la Llera-Moya, M., Yuen, T. L., Rothblat, G. H., Billheimer, J. T., & Rader, D. J. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.177105 · Cited by 63
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“04 Congestive heart failure 82 (28) 90 (31) 121 (42) 119 (41) ,0.”
BackgroundHigh-Density Lipoproteins Potentiate α1-Antitrypsin Therapy in Elastase-Induced Pulmonary Emphysema
Moreno, J. A., Ortega‐Gómez, A., Rubio‐Navarro, A., Louedec, L., Ho‐Tin‐Noé, B., Caligiuri, G., Nicoletti, A., Levoye, A., Plantier, L., & Meilhac, O. (2014) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2013-0103oc · Cited by 63
“HDL may thus represent a vector for proteins or peptides reported to be naturally associated with it, because of their affinity for HDL particles (8, 9).”
BackgroundThe small HDL particle hypothesis of Alzheimer's disease
Martinez, A. E., Weissberger, G. H., Kuklenyik, Z., He, X., Meuret, C. J., Parekh, T., Rees, J. C., Parks, B. A., Gardner, M. S., King, S. M., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12649 · Cited by 63
Functional and proteomic alterations of plasma high density lipoproteins in type 1 diabetes mellitus
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“Despite clear epidemiologic evidence that lowserumHDL cholesterol (HDL-C) concentrations are a risk factor for atherosclerosis and cardiovascular disease (1), no clinical trial aiming at raising HDL-C has been successful in reducing risk (2).”
BackgroundGordon, S. M., McKenzie, B. A., Kemeh, G., Sampson, M. L., Perl, S., Young, N. S., Fessler, M. B., & Remaley, A. T. (2015) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m115.054031 · Cited by 61
“teins among its particle subclasses (5, 6, 7, 8, 9).”
BackgroundResultMarsillach, J., Becker, J. O., Vaisar, T., Hahn, B. H., Brunzell, J. D., Furlong, C. E., de Boer, I. H., McMahon, M. A., Hoofnagle, A. N., & DCCT/EDIC Research Group (2015) · Journal of Proteome Research · doi:10.1021/pr5011586 · Cited by 60
Self-citationApoA-I/HDL-C levels are inversely associated with abdominal aortic aneurysm progression
Molina-Sánchez, P., Jorge, I., Martínez-Pinna, R., Blanco‐Colio, L. M., Tarín, C., Torres-Fonseca, M. M., Esteban, M., Laustsen, J., Ramos‐Mozo, P., Calvo, E., et al. (2015) · Thrombosis and Haemostasis · doi:10.1160/th14-10-0874 · Cited by 61
“Proteomic analysis of HDL has demonstrated that these particles transport serpins with serine-type endopeptidase inhibitor activity that protect against proteolytic degradation of the tissue (36, 37).”
BackgroundThe protein cargo of HDL: Implications for vascular wall biology and therapeutics
Heinecke, J. W. (2010) · Journal of clinical lipidology · doi:10.1016/j.jacl.2010.08.005 · Cited by 59
“Our proteomic analyses of HDL produced several unanticipated observations (19).”
BackgroundMethodInfluentialSelf-citationRonsein, G. E., Hutchins, P. M., Isquith, D. A., Vaisar, T., Zhao, X.-Q., & Heinecke, J. W. (2015) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.115.306268 · Cited by 60
Self-citationCD5L as an Extracellular Vesicle-Derived Biomarker for Liquid Biopsy of Lung Cancer
Choi, E., Faruque, H. A., Kim, J., Kim, K. J., Choi, J. E., Kim, B. A., Kim, B., Kim, Y. J., Woo, M. H., Park, J. Y., et al. (2021) · Diagnostics · doi:10.3390/diagnostics11040620 · Cited by 58
Spotlight on HDL-raising therapies: insights from the torcetrapib trials
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“In addition, they carry multiple proteins involved in inflammatory response, innate immunity and complement activation”
BackgroundApolipoprotein A-I and A-I mimetic peptides: a role in atherosclerosis
Getz, G. S., & Reardon (2011) · Journal of Inflammation Research · doi:10.2147/jir.s12983 · Cited by 59
Mazer, N. A., Giulianini, F., Paynter, N. P., Jordan, P., & Mora, S. (2013) · Clinical Chemistry · doi:10.1373/clinchem.2012.196949 · Cited by 59
Role of Adhesion in Arthropod Immune Recognition
Schmidt, O., Söderhäll, K., Theopold, U., & Faye, I. (2009) · Annual Review of Entomology · doi:10.1146/annurev.ento.54.110807.090618 · Cited by 58
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“Reduced Pon1 activity is associated with increased oxidative stress and CVD in humans and with atherogenesis in mice [28,35,36].”
BackgroundDysfunctional HDL: From Structure-Function-Relationships to Biomarkers
Riwanto, M., Rohrer, L., von Eckardstein, A., & Landmesser, U. (2014) · Handbook of experimental pharmacology · doi:10.1007/978-3-319-09665-0_10 · Cited by 60
“In the study by Vaisar et al., HDL was shown to carry apolipoproteins and proteins with functions in lipid metabolism, the acute phase response, complement regulation, and blood coagulation (Vaisar et al. 2007).”
BackgroundMethodResultInfluentialDistinct composition of human fetal HDL attenuates its anti-oxidative capacity
Sreckovic, I., Birner‐Gruenberger, R., Obrist, B., Stojaković, T., Scharnagl, H., Holzer, M., Scholler, M., Philipose, S., Marsche, G., Lang, U., et al. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2012.12.015 · Cited by 58
HDL and immunomodulation: an emerging role of HDL against atherosclerosis
Yu, B., Wang, S., Peng, D., & Zhao, S. (2010) · Immunology and Cell Biology · doi:10.1038/icb.2009.112 · Cited by 58
High-Density Lipoprotein Mediated Cellular Cholesterol Efflux in Acute Coronary Syndromes
Hafiane, A., Jabor, B., Ruel, I. L., Ling, J., & Genest, J. J. (2013) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2013.09.006 · Cited by 59
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Filou, S., Lhomme, M., Karavia, E. A., Kalogeropoulou, C. P., Theodoropoulos, V., Zvintzou, E., Sakellaropoulos, G. C., Πετροπούλου, Π.-Ι., Constantinou, C., Kontush, A., et al. (2016) · Biochemistry · doi:10.1021/acs.biochem.6b00389 · Cited by 60
“This observation is in agreement with recent proteomic studies (10-14) in centrifugally-”
ResultGordon, S. M., Chung, J. H. N., Playford, M. P., Dey, A. K., Sviridov, D. O., Seifuddin, F., Chen, Y., Pirooznia, M., Chen, M. Y., Mehta, N. N., et al. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.09.032 · Cited by 59
“It is important to note that the proteins associated with HDL can vary, depending on the isolation procedure [43, 47].”
BackgroundShao, B., de Boer, I. H., Tang, C., Mayer, P. S., Zelnick, L. R., Afkarian, M., Heinecke, J. W., & Himmelfarb, J. (2015) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5b00060 · Cited by 57
Self-citationSacks, F. M., Liang, L., Furtado, J. D., Cai, T., Davidson, W. S., He, Z., McClelland, R. L., Rimm, E. B., & Jensen, M. K. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.120.314609 · Cited by 57
“HDL-cholesterol, mg/dL; mean (SD) 62 (16) 44 (11) 55 (20) 45 (11) 57 (16) ND 44 (12)”
Pamir, N., Hutchins, P. M., Ronsein, G. E., Vaisar, T., Reardon, C. A., Getz, G. S., Lusis, A. J., & Heinecke, J. W. (2015) · Journal of Lipid Research · doi:10.1194/jlr.m063701 · Cited by 55
Self-citationDeepening our understanding of HDL proteome
Ronsein, G. E., & Vaisar, T. (2019) · Expert Review of Proteomics · doi:10.1080/14789450.2019.1650645 · Cited by 57
Self-citationMacrophage Scavenger Receptor A Mediates Adhesion to Apolipoproteins A-I and E
Neyen, C. D., Plüddemann, A., Roversi, P., Thomas, B., Cai, L., van der Westhuyzen, D. R., Sim, R. B., & Gordon, S. (2009) · Biochemistry · doi:10.1021/bi9013769 · Cited by 56
“identified proteins involved in the acute phase response, proteinase inhibition, and complement regulation in addition to lipid metabolism (34).”
Detrimental Effect of Hypercholesterolemia on High-Density Lipoprotein Particle Remodeling in Pigs
Padró, T., Cubedo, J., Camino-López, S., Béjar, M. T., Ben‐Aicha, S., Mendieta, G., Escolá‐Gil, J. C., Escate, R., Gutiérrez, M., Casaní, L., et al. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.05.018 · Cited by 57
Liu, C., Zhang, N., Yu, H., Chen, Y., Liang, Y., Deng, H., & Zhang, Z. (2010) · Placenta · doi:10.1016/j.placenta.2010.11.007 · Cited by 55
“ApoA2, ApoH and SAA4 were also linked to acute-phase response [15,16].”
BackgroundHigh-Density Lipoprotein Carries Markers That Track With Recovery From Stroke
Plubell, D. L., Fenton, A. M., Rosário, S., Bergstrom, P., Wilmarth, P. A., Clark, W. M., Zakai, N. A., Quinn, J. F., Minnier, J., Alkayed, N. J., et al. (2020) · Circulation Research · doi:10.1161/circresaha.120.316526 · Cited by 56
Reduced Apolipoprotein Glycosylation in Patients with the Metabolic Syndrome
Savinova, O. V., Fillaus, K., Jing, L., Harris, W. S., & Shearer, G. C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104833 · Cited by 55
“Some evidence of apo composition of lipoprotein classes in MetSyn is available from the proteomic studies: thus, HDL (HDL3 subclass) isolated from dyslipidemic subjects (with new diagnosis of coronary artery disease) were reported to be enriched in apoE [18]; whereas LDL”
Lepedda, A. J., Nieddu, G., Zinellu, E., Muro, P. D., Piredda, F., Guarino, A., Spirito, R., Carta, F., Turrini, F. M., & Formato, M. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/385214 · Cited by 53
Nakamura, N., Hatano, E., Iguchi, K., Sato, M., Kawaguchi, H., Ohtsu, I., Sakurai, T., Aizawa, N., Iijima, H., Nishiguchi, S., et al. (2019) · BMC Cancer · doi:10.1186/s12885-019-5825-8 · Cited by 54
Wang, Y., Ghoshal, S., Ward, M. R., de Villiers, W. J. S., Woodward, J. G., & Eckhardt, E. R. M. (2010) · PLoS ONE · doi:10.1371/annotation/bc95caf3-62cf-4ecd-8a79-9116e62f4a50 · Cited by 54
An altered pattern of circulating apolipoprotein E3 isoforms is implicated in preeclampsia
Atkinson, K. R., Blumenstein, M., Black, M. A., Wu, S., Kasabov, N. K., Taylor, R. S., Cooper, G. J. S., & North, R. A. (2008) · Journal of Lipid Research · doi:10.1194/jlr.m800296-jlr200 · Cited by 53
Nicholls, S. J., Ruotolo, G., Brewer, H. B., Wang, M.-D., Liu, L., Willey, M. B., Deeg, M. A., Krueger, K. A., & Nissen, S. E. (2015) · Journal of clinical lipidology · doi:10.1016/j.jacl.2015.11.014 · Cited by 53
Xu, C., Chen, Y., Xu, L., Miao, M., Li, Y., & Yu, C. (2016) · Scientific Reports · doi:10.1038/srep23279 · Cited by 53
High-density Lipoprotein and Inflammation and Its Significance to Atherosclerosis
Hu, J., Xi, D., Zhao, J., Luo, T., Liu, J., Lu, H., Li, M., Xiong, H., & Guo, Z. (2016) · The American Journal of the Medical Sciences · doi:10.1016/j.amjms.2016.06.014 · Cited by 53
“Those results supported the findings of previous studies suggesting that HDL may regulate complement activation.(30,31) Several recent studies have provided new insight into the mechanism by which HDL exerts atheroprotective effects via the modulation of the complement system.”
ResultShao, B., & Heinecke, J. W. (2017) · Expert Review of Proteomics · doi:10.1080/14789450.2018.1402680 · Cited by 55
Self-citationHigh-Density Lipoprotein Function in Cardiovascular Disease and Diabetes Mellitus
He, Y., Kothari, V. M., & Bornfeldt, K. (2018) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.310222 · Cited by 56
“The heterogeneous population of HDL particles may collectively contain >95 different proteins.(50,51) Each HDL subspecies can have distinct functions and may be metabolized through different pathways in humans.”
BackgroundCheung, M. C., Vaisar, T., Han, X., Heinecke, J. W., & Albers, J. J. (2010) · Biochemistry · doi:10.1021/bi100359f · Cited by 53
“Of these 24 proteins, 6 (vitamin K-dependent protein S, perlecan, fibrinogen-like protein 1, ficolin-2, plexin domain-containing protein 2, and mannan-binding lectin serine protease) were not previously known to reside in HDL (25,26,45).”
BackgroundMethodSelf-citationTan, Y., Liu, T. R., Hu, S. W., Tian, D., Li, C., Zhong, J. K., Sun, H. G., Luo, T., Lai, W. Y., & Guo, Z. (2014) · PLoS ONE · doi:10.1371/journal.pone.0094264 · Cited by 51
Yassine, H. N., Borges, C. R., Schaab, M. R., Billheimer, D. D., Stump, C. S., Reaven, P. D., Lau, S. S., & Nelson, R. W. (2013) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.201200028 · Cited by 51
“[72] not only demonstrated both a remarkable diversity of proteins and peptides identified within HDL, but also reported a high representation of proteins involved in nonlipid transport functions, including acute phase response, complement regulation, proteolysis, and coagulation.”
BackgroundPaun, C. C., Ersoy, L., Schick, T., Groenewoud, J. M. M., Lechanteur, Y. T. E., Fauser, S., Hoyng, C. B., de Jong, E. K., & den Hollander, A. I. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.15-17035 · Cited by 51
“Recent proteomic analyses revealed several types of HDL particles containing complement system components C4a, C4b, C9, and vitronectin(63,64) in healthy subjects, and C3 in patients with coronary artery disease.(63) In our study, we offer support for this emerging concept by demonstrating a significant correlation be…”
Time to ditch HDL-C as a measure of HDL function?
Ronsein, G. E., & Heinecke, J. W. (2017) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000446 · Cited by 51
Self-citationMasson, P., & Rochu, D. (2009) · Acta Naturae · doi:10.32607/20758251-2009-1-1-68-78 · Cited by 50
High-Density Lipoprotein Functionality in Coronary Artery Disease
Kosmas, C. E., Christodoulidis, G., Cheng, J.-W., Lerakis, S., & Vittorio, T. J. (2014) · The American Journal of the Medical Sciences · doi:10.1097/maj.0000000000000231 · Cited by 49
“Whereas, mass spectrometry studies have shown that the HDL particles carry multiple proteins, which are not only involved in lipid metabolism but also play a role in complement regulation, acute phase response and proteinase inhibition.(20) Lipidomic approaches have provided initial insights into the HDL lipidome with…”
BackgroundDysfunctional HDL in acute stroke
Ortiz-Munoz, G., Couret, D., Lapergue, B., Bruckert, É., Meseguer, E., Amarenco, P., & Meilhac, O. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.08.035 · Cited by 51
Qu, L., Guennel, T., & Marshall, S. L. (2013) · Biometrics · doi:10.1111/biom.12095 · Cited by 47
Hamad, I. M., Hunter, A. C., & Moghimi, S. M. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.05.030 · Cited by 49
Pleiotropic effects of apolipoprotein C3 on HDL functionality and adipose tissue metabolic activity
Zvintzou, E., Lhomme, M., Chasapi, S., Filou, S., Theodoropoulos, V., Xapapadaki, E., Kontush, A., Spyroulias, G. A., Tellis, C. C., Tselepis, A. D., et al. (2017) · Journal of Lipid Research · doi:10.1194/jlr.m077925 · Cited by 48
HDL Lipids and Insulin Resistance
Hoofnagle, A. N., Vaisar, T., Mitra, P., & Chait, A. (2010) · Current Diabetes Reports · doi:10.1007/s11892-009-0085-7 · Cited by 49
“Some proteins found in HDL from subjects with cardiovascular disease appear to be cellular proteins [ 6 ].”
BackgroundSelf-citationDrug Treatment of Hyperlipidaemia
Toth, P. P. (2010) · Drugs · doi:10.2165/10898610-000000000-00000 · Cited by 49
“cholesteryl ester transfer protein), oxidationreduction enzymes (paraoxonase, platelet-activating factor acetyl hydrolase, glutathione peroxidase), acute phase reactants (serum amyloid A, fibrinogen), apolipoproteins and immunity factors (complement proteins), among many others.([23,24])”
BackgroundHDL Metabolism and CETP Inhibition
Barkowski, R. S., & Frishman, W. H. (2008) · Cardiology in Review · doi:10.1097/crd.0b013e31816a3b60 · Cited by 49
“the idea that HDLs atheroprotective ability extends beyond RCT and entails contributions to the innate immune system as well.(20) Eventually these proteins can become biomarkers to measure the outcome of pharmacologically altering HDL levels and function.”
BackgroundBeneficial effects of omega-3 fatty acids in the proteome of high-density lipoprotein proteome
Burillo, E., Mateo‐Gállego, R., Cenarro, A., Fiddyment, S., Bea, A. M., Jorge, I., Vázquez, J., & Civeira, F. (2012) · Lipids in Health and Disease · doi:10.1186/1476-511x-11-116 · Cited by 48
“of lipoprotein oxidation [10,11], regulation of the complement system, inhibition of proteolysis and regulation of acute phase response [12].”
BackgroundKhersonsky, O., Rosenblat, M., Toker, L., Yacobson, S., Hugenmatter, A., Silman, I., Sussman, J. L., Aviram, M., & Tawfik, D. S. (2009) · Biochemistry · doi:10.1021/bi900583y · Cited by 48
“A substantial fraction of PON3 is HDL-associated in rabbit (35) and human serum (36), but its interactions with HDL have not been studied before.”
BackgroundThe Structure of Dimeric Apolipoprotein A-IV and Its Mechanism of Self-Association
Deng, X., Morris, J. C., Dressmen, J., Tubb, M. R., Tso, P., Jerome, W. G., Davidson, W. S., & Thompson, T. B. (2012) · Structure · doi:10.1016/j.str.2012.02.020 · Cited by 48
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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