Aside from a decrease in the high-density lipoprotein (HDL) cholesterol levels, qualitative abnormalities of HDL can contribute to an increase in cardiovascular (CV) risk in end-stage renal disease (ESRD) patients undergoing chronic hemodialysis (HD). Dysfunctional HDL leads to an alteration of reverse cholesterol transport and the antioxidant and anti-inflammatory properties of HDL. In this study, a quantitative proteomics approach, based on iTRAQ labeling and nanoflow liquid chromatography mass spectrometry analysis, was used to generate detailed data on HDL-associated proteins. The HDL composition was compared between seven chronic HD patients and a pool of seven healthy controls. To confirm the proteomics results, specific biochemical assays were then performed in triplicate in the 14 samples as well as 46 sex-matched independent chronic HD patients and healthy volunteers. Of the 122 proteins identified in the HDL fraction, 40 were differentially expressed between the healthy volunteers and the HD patients. These proteins are involved in many HDL functions, including lipid metabolism, the acute inflammatory response, complement activation, the regulation of lipoprotein oxidation, and metal cation homeostasis. Among the identified proteins, apolipoprotein C-II and apolipoprotein C-III were significantly increased in the HDL fraction of HD patients whereas serotransferrin was decreased. In this study, we identified new markers of potential relevance to the pathways linked to HDL dysfunction in HD. Proteomic analysis of the HDL fraction provides an efficient method to identify new and uncharacterized candidate biomarkers of CV risk in HD patients.
References
[1]
Ansell BJ, Navab M, Hama S, Kamranpour N, Fonarow G, et al. (2003) Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 108: 2751–2756.
[2]
Kontush A, Chapman MJ (2006) Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev 58: 342–374.
[3]
Watson AD, Berliner JA, Hama SY, La Du BN, Faull KF, et al. (1995) Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest 96: 2882–2891.
[4]
Feig JE, Shamir R, Fisher EA (2008) Atheroprotective effects of HDL: beyond reverse cholesterol transport. Curr Drug Targets 9: 196–203.
[5]
Ansell BJ, Fonarow GC, Fogelman AM (2007) The paradox of dysfunctional high-density lipoprotein. Curr Opin Lipidol 18: 427–434.
[6]
Yu R, Yekta B, Vakili L, Gharavi N, Navab M, et al. (2008) Proatherogenic high-density lipoprotein, vascular inflammation, and mimetic peptides. Curr Atheroscler Rep 10: 171–176.
[7]
G HB, Rao VS, Kakkar VV (2011) Friend Turns Foe: Transformation of Anti-Inflammatory HDL to Proinflammatory HDL during Acute-Phase Response. Cholesterol 2011: 274629.
[8]
Morena M, Delbosc S, Dupuy AM, Canaud B, Cristol JP (2005) Overproduction of reactive oxygen species in end-stage renal disease patients: a potential component of hemodialysis-associated inflammation. Hemodial Int 9: 37–46.
[9]
Nguyen AT, Lethias C, Zingraff J, Herbelin A, Naret C, et al. (1985) Hemodialysis membrane-induced activation of phagocyte oxidative metabolism detected in vivo and in vitro within microamounts of whole blood. Kidney Int 28: 158–167.
[10]
Peuchant E, Carbonneau MA, Dubourg L, Thomas MJ, Perromat A, et al. (1994) Lipoperoxidation in plasma and red blood cells of patients undergoing haemodialysis: vitamins A, E, and iron status. Free Radic Biol Med 16: 339–346.
[11]
Stenvinkel P, Alvestrand A (2002) Inflammation in end-stage renal disease: sources, consequences, and therapy. Semin Dial 15: 329–337.
[12]
Vaziri ND (2006) Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences. Am J Physiol Renal Physiol 290: F262–272.
[13]
Attman PO, Alaupovic P (1991) Lipid and apolipoprotein profiles of uremic dyslipoproteinemia–relation to renal function and dialysis. Nephron 57: 401–410.
[14]
Sutherland WH, Corboy J, Walker RJ, Robertson MC, Ball MJ (1995) Cell cholesterol transport to plasma in blood from patients with renal failure or a kidney transplant. Nephrol Dial Transplant 10: 358–365.
[15]
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY (2004) Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351: 1296–1305.
[16]
Muntner P, He J, Astor BC, Folsom AR, Coresh J (2005) Traditional and nontraditional risk factors predict coronary heart disease in chronic kidney disease: results from the atherosclerosis risk in communities study. J Am Soc Nephrol 16: 529–538.
[17]
Deighan CJ, Caslake MJ, McConnell M, Boulton-Jones JM, Packard CJ (2000) Atherogenic lipoprotein phenotype in end-stage renal failure: origin and extent of small dense low-density lipoprotein formation. Am J Kidney Dis 35: 852–862.
[18]
Montazerifar F, Hashemi M, Karajibani M, Dikshit M (2010) Hemodialysis alters lipid profiles, total antioxidant capacity, and vitamins A, E, and C concentrations in humans. J Med Food 13: 1490–1493.
[19]
Holzer M, Birner-Gruenberger R, Stojakovic T, El-Gamal D, Binder V, et al. (2011) Uremia alters HDL composition and function. J Am Soc Nephrol 22: 1631–1641.
[20]
Jurek A, Turyna B, Kubit P, Klein A (2008) The ability of HDL to inhibit VCAM-1 expression and oxidized LDL uptake is impaired in renal patients. Clin Biochem 41: 1015–1018.
[21]
Moradi H, Pahl MV, Elahimehr R, Vaziri ND (2009) Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. Transl Res 153: 77–85.
[22]
Morena M, Cristol JP, Dantoine T, Carbonneau MA, Descomps B, et al. (2000) Protective effects of high-density lipoprotein against oxidative stress are impaired in haemodialysis patients. Nephrol Dial Transplant 15: 389–395.
[23]
Tang WH, Shilov IV, Seymour SL (2008) Nonlinear fitting method for determining local false discovery rates from decoy database searches. J Proteome Res 7: 3661–3667.
[24]
Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, et al. (2003) DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4: P3.
[25]
Davidson WS, Silva RA, Chantepie S, Lagor WR, Chapman MJ, et al. (2009) Proteomic analysis of defined HDL subpopulations reveals particle-specific protein clusters: relevance to antioxidative function. Arterioscler Thromb Vasc Biol 29: 870–876.
[26]
Gordon SM, Deng J, Lu LJ, Davidson WS (2010) Proteomic Characterization of Human Plasma High Density Lipoprotein Fractionated by Gel Filtration Chromatography. J Proteome Res 9: 5239–5249.
[27]
Karlsson H, Leanderson P, Tagesson C, Lindahl M (2005) Lipoproteomics II: mapping of proteins in high-density lipoprotein using two-dimensional gel electrophoresis and mass spectrometry. Proteomics 5: 1431–1445.
Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, et al. (2007) Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest 117: 746–756.
[30]
Davidsson P, Hulthe J, Fagerberg B, Camejo G (2010) Proteomics of apolipoproteins and associated proteins from plasma high-density lipoproteins. Arterioscler Thromb Vasc Biol 30: 156–163.
[31]
Hoofnagle AN, Heinecke JW (2009) Lipoproteomics: using mass spectrometry-based proteomics to explore the assembly, structure, and function of lipoproteins. J Lipid Res 50: 1967–1975.
[32]
Jong MC, Hofker MH, Havekes LM (1999) Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler Thromb Vasc Biol 19: 472–484.
[33]
Bukberg PR, Le NA, Ginsberg HN, Gibson JC, Rubinstein A, et al. (1985) Evidence for non-equilibrating pools of apolipoprotein C-III in plasma lipoproteins. J Lipid Res 26: 1047–1057.
[34]
Tian L, Wu J, Fu M, Xu Y, Jia L (2009) Relationship between apolipoprotein C-III concentrations and high-density lipoprotein subclass distribution. Metabolism 58: 668–674.
[35]
Shao B, Oda MN, Oram JF, Heinecke JW (2006) Myeloperoxidase: an inflammatory enzyme for generating dysfunctional high density lipoprotein. Curr Opin Cardiol 21: 322–328.
[36]
McGillicuddy FC, de la Llera Moya M, Hinkle CC, Joshi MR, Chiquoine EH, et al. (2009) Inflammation impairs reverse cholesterol transport in vivo. Circulation 119: 1135–1145.
[37]
Blokhina O, Virolainen E, Fagerstedt KV (2003) Antioxidants, oxidative damage and oxygen deprivation stress: a review. Ann Bot 91 Spec No: 179–194.
[38]
Weinstein T, Chagnac A, Korzets A, Boaz M, Ori Y, et al. (2000) Haemolysis in haemodialysis patients: evidence for impaired defence mechanisms against oxidative stress. Nephrol Dial Transplant 15: 883–887.
[39]
Katoh N, Nakagawa H (1999) Detection of haptoglobin in the high-density lipoprotein and the very high-density lipoprotein fractions from sera of calves with experimental pneumonia and cows with naturally occurring fatty liver. J Vet Med Sci 61: 119–124.
[40]
Nielsen MJ, Petersen SV, Jacobsen C, Oxvig C, Rees D, et al. (2006) Haptoglobin-related protein is a high-affinity hemoglobin-binding plasma protein. Blood 108: 2846–2849.
[41]
Chua AC, Graham RM, Trinder D, Olynyk JK (2007) The regulation of cellular iron metabolism. Crit Rev Clin Lab Sci 44: 413–459.
[42]
Kunitake ST, Jarvis MR, Hamilton RL, Kane JP (1992) Binding of transition metals by apolipoprotein A-I-containing plasma lipoproteins: inhibition of oxidation of low density lipoproteins. Proc Natl Acad Sci U S A 89: 6993–6997.
