In vitro stimulation of HDL anti-inflammatory activity and inhibition of LDL pro-inflammatory activity in the plasma of patients with end-stage renal disease by an apoA-1 mimetic peptide
2009; Elsevier BV; Volume: 76; Issue: 4 Linguagem: Inglês
10.1038/ki.2009.177
ISSN1523-1755
AutoresNosratola D. Vaziri, Hamid Moradi, Madeleine V. Pahl, Alan M. Fogelman, Mohamad Navab,
Tópico(s)Lipoproteins and Cardiovascular Health
ResumoFeatures of end-stage renal disease such as oxidative stress, inflammation, hypertension, and dyslipidemia are associated with accelerated atherosclerosis and increased risk of death from cardiovascular disease. By inhibiting the formation and increasing the disposal of oxidized lipids, HDL exerts potent antioxidant and anti-inflammatory actions. Given that apolipoproteinA-1 can limit atherosclerosis, we hypothesized that an apolipoproteinA-1 mimetic peptide, 4F, may reduce the proinflammatory properties of LDL and enhance the anti-inflammatory properties of HDL in uremic plasma. To test this, plasma from each of 12 stable hemodialysis patients and age-matched control subjects was incubated with 4F or vehicle. The isolated HDL and LDL fractions were added to cultured human aortic endothelial cells to quantify monocyte chemotactic activity, thus measuring their pro- or anti-inflammatory index. The LDL from the hemodialysis patients was more pro-inflammatory and their HDL was less anti-inflammatory than those of the control subjects. Pre-incubation of the plasma from the hemodialysis patients with 4F decreased LDL pro-inflammatory activity and enhanced HDL anti-inflammatory activity. Whether 4F or other apolipoproteinA-1 mimetic peptides will have any therapeutic benefit in end-stage renal disease will have to be examined directly in clinical studies. Features of end-stage renal disease such as oxidative stress, inflammation, hypertension, and dyslipidemia are associated with accelerated atherosclerosis and increased risk of death from cardiovascular disease. By inhibiting the formation and increasing the disposal of oxidized lipids, HDL exerts potent antioxidant and anti-inflammatory actions. Given that apolipoproteinA-1 can limit atherosclerosis, we hypothesized that an apolipoproteinA-1 mimetic peptide, 4F, may reduce the proinflammatory properties of LDL and enhance the anti-inflammatory properties of HDL in uremic plasma. To test this, plasma from each of 12 stable hemodialysis patients and age-matched control subjects was incubated with 4F or vehicle. The isolated HDL and LDL fractions were added to cultured human aortic endothelial cells to quantify monocyte chemotactic activity, thus measuring their pro- or anti-inflammatory index. The LDL from the hemodialysis patients was more pro-inflammatory and their HDL was less anti-inflammatory than those of the control subjects. Pre-incubation of the plasma from the hemodialysis patients with 4F decreased LDL pro-inflammatory activity and enhanced HDL anti-inflammatory activity. 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In an attempt to overcome these limitations, a series of synthetic short apoA-1 mimetic peptides have been developed, which have proven to be highly effective in attenuating atherosclerosis in experimental animals. Comprehensive assessment of the physical–chemical characteristics of these peptides has revealed the critical role of the hydrophobic region in their biological activity. Administration of the apoA-1 mimetic peptide, 4F, has been shown to significantly improve HDL function in mice and monkeys,39.Navab M. Anantharamaiah G.M. Hama S. et al.D-4F and statins synergize to render HDL anti-inflammatory in mice and monkeys and cause lesion regression in old apolipoprotein E-null mice.Arterioscler Thromb Vasc Biol. 2005; 25: 1426-1432Crossref PubMed Scopus (139) Google Scholar,40.Navab M. Anantharamaiah G.M. 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Reddy S.T. et al.Apolipoprotein A-I mimetic peptides and their role in atherosclerosis prevention.Nat Clin Pract Cardiovasc Med. 2006; 3: 540-547Crossref PubMed Scopus (106) Google Scholar In view of the documented LDL and HDL abnormalities in CKD and demonstrated efficacy of apoA-1 I mimetic peptides in experimental animals, we hypothesized that ApoA-1 I mimetic peptide may reduce the proinflammatory properties of LDL and enhance anti-inflammatory properties of HDL in uremic plasma. To test this hypothesis, plasma from 12 ESRD patients and 12 control individuals were treated with 4F or vehicle, HDL and LDL fractions were then isolated and added to cultures of human aortic endothelial cells and the resulting monocyte chemotactic activity was quantified. General data are shown in Table 1. The ESRD group showed marked elevations of plasma creatinine and urea nitrogen and a significant reduction of blood hemoglobin and plasma HDL-cholesterol level and a moderate reduction of total cholesterol concentration.Table 1Age, gender, serum creatinine, urea nitrogen, total cholesterol, HDL-cholesterol, and Hgb concentrations in the ESRD and control groups, as well as Kt/V in the ESRD groupControlESRDAge47.7±3.252.7±4.3Male/female6/65/7Creatinine (mg per 100 ml)0.8±0.18.81±0.65***P<0.005.BUN (mg per 100 ml)13±0.868.3±4.1***P<0.005.Hgb (g per 100 ml)14.4±0.4111.1±0.33***P<0.005.Total cholesterol (mg per 100 ml)160±1.6137±6.6HDL-cholesterol (mg per 100 ml)46.6±2.438.0±1.7*P<0.05,Kt/VNA1.54±0.06BUN, blood urea nitrogen; ESRD, end-stage renal disease; HDL, high-density lipoprotein; Hgb, blood hemoglobin; NA, not applicable.* P<0.05,*** P<0.005. Open table in a new tab BUN, blood urea nitrogen; ESRD, end-stage renal disease; HDL, high-density lipoprotein; Hgb, blood hemoglobin; NA, not applicable. The ESRD group showed marked elevations of plasma, tumor necrosis factor-α, interleukin (IL)-6, and IL-8 (Table 2) and significant increases in plasma malondialdehyde (MDA) and carbonylated proteins (Table 2), pointing to the presence of systemic oxidative stress and inflammation.Table 2Plasma concentrations of MDA, protein carbonyl, IL6, IL-8, and TNF-α in the ESRD and control groupsControlESRDMDA (μmol/l)1.09±0.091.87±0.07***P<0.005.Protein carbonyl content (nmol/mg)0.49±0.8210.8±3.3*P<0.05,IL-6 (pg/ml)1.43±0.365.80±1.4*P<0.05,TNF-α (pg/ml)2.01±0.3310.64 ±1.4***P<0.005.IL-8 (pg/ml)1.87±0.385.70±0.34***P<0.005.ESRD, end-stage renal disease; IL, interleukin; MDA, malondialdehyde; TNF-α, tumor necrosis factor.* P<0.05,*** P<0.005. Open table in a new tab ESRD, end-stage renal disease; IL, interleukin; MDA, malondialdehyde; TNF-α, tumor necrosis factor. The reduction of HDL-cholesterol level was accompanied by a marked reduction of serum apoA-1 and lecithin:cholesterol acyltransferase (LCAT) concentrations (Table 3). This was also accompanied by significant reductions of plasma paraoxonase and glutathione peroxidase (GPX) activities in the ESRD group (Table 3).Table 3Plasma concentrations of apo-A1 and LCAT and activities of paraoxonase and GPX in the ESRD and control groupsControlESRDApoA-I (nmol/mg)158.2±30.372.2±7.6*P<0.05,LCAT (pg/ml)7.6±0.474.7±0.54***P<0.005.Paraoxonase activity (pg/ml)143.1±17.391.2±7.4*P<0.05,GPX activity (pg/ml)531.0±63.7227.5±13.4***P<0.005.ESRD, end-stage renal disease; ApoA-1, apolipoprotein-A1; GPX, glutathione peroxidase; LCAT, lecithin cholesterol acyltransferase.* P<0.05,*** P<0.005. Open table in a new tab ESRD, end-stage renal disease; ApoA-1, apolipoprotein-A1; GPX, glutathione peroxidase; LCAT, lecithin cholesterol acyltransferase. As expected, addition of normal HDL lowered the pro-oxidant activity of the standard oxidized LDL substrate used in this assay. In contrast, HDL from ESRD patients failed to lower the pro-oxidant activity of the standard oxidized LDL, and on average increased it (Figure 1). Low-density lipoprotein isolated from the ERSD patients was markedly proinflammatory compared with LDL isolated from the control group (Figure 2). Treatment of ERSD plasma in vitro with the apoA-1 mimetic peptide 4F significantly reduced the inflammatory properties of the ERSD LDL (Figure 2). High-density lipoprotein isolated from ERSD plasma was highly proinflammatory and was markedly less proinflammatory after treatment of the ERSD plasma with 4F in vitro (Figure 3). HDL isolated from ERSD plasma was proinflammatory in both diabetic and non-diabetic patients (data not shown), suggesting a dominant role of ESRD. To determine the effect of L-4F on HDL-inflammatory index of normal individuals, we prepared plasma from an additional group of 10 normal healthy individuals (five male and five female, aged 47±11.7 years). These samples were sham treated or treated with L-4F in vitro and the HDL-inflammatory index was determined as described in Materials and Methods. As shown in Figure 4, the untreated HDL in these normal healthy individuals was anti-inflammatory (HDL-inflammatory index=0.43±0.05) and was rendered more anti-inflammatory after treatment with L-4F in vitro (HDL-inflammatory index=0.20±0.04).Figure 4L-4F improves the HDL-inflammatory index of normal plasma. Plasma was obtained from 10 normal healthy individuals aged 47.2±11.7 years (five male and five female individuals) and was sham-treated or treated with L-4F and the HDL-inflammatory index was determined as described in the Materials and Methods section.View Large Image Figure ViewerDownload (PPT) As expected plasma HDL-cholesterol concentration was significantly reduced in ESRD patients as compared with that found in the control group. This was associated with marked reductions of plasma apoA-1 and LCAT concentrations. LCAT is a key HDL-associated enzyme, which catalyzes conversion of cell-derived free cholesterol to cholesterol ester on the surface of HDL. This process depends on the dual function of LCAT as phopholipase-2, which catalyzes hydrolysis and release of the SN-2 fatty acid in the phospholipid molecule, and as Acyl-CoA cholesterol acyltransferase, which catalyzes esterification of free cholesterol with the fatty acid generated by the latter reaction.49.Glomset J.A. The plasma lecithins:cholesterol acyltransferase reaction.J Lipid Res. 1968; 9: 155-167Abstract Full Text PDF PubMed Google Scholar LCAT-mediated conversion of amphipathic-free cholesterol to hydrophobic cholesterol ester results in the shift of cholesterol from the surface into the core of HDL. This process is critical for maintaining favorable gradient for maximal uptake of cholesterol by HDL, maturation of lipid-poor nascent HDL to cholesterol ester-rich HDL-2, and efficiency of reverse cholesterol transport. Thus, the observed LCAT deficiency contributes to diminished HDL-cholesterol content, impaired HDL maturation, and defective reverse cholesterol transport in patients with advanced CKD. The reduction of plasma LCAT concentration found in the ESRD patients used in this study extends the findings of earlier studies, which showed diminished plasma LCAT enzymatic activity in ESRD patients50.Vaziri N.D. Liang K. Parks J.S. 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Downregulation of hepatic lecithin:cholesterol acyltransferase (LCAT) gene expression in chronic renal failure.Kidney Int. 2001; 59: 2192-2196Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The reduction in HDL concentration in the ESRD group was compounded by severe reduction of its antioxidant capacity confirming recent studies.33.Moradi H. Pahl M.V. Elahimehr R. et al.Impaired Antioxidant Activity of HDL in Chronic Kidney Disease.Translational Res. 2009; 153: 77-85Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar,34.Kalantar-Zadeh K. Kopple J.D. Kamranpour N. et al.HDL-inflammatory index correlates with poor outcome in hemodialysis patients.Kidney Int. 2007; 72: 1149-1156Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar This was associated with marked reduction of paraoxonase and GPX enzyme activity in the study population. Paraoxonase and GPX are major HDL-associated antioxidant enzymes that catalyze reduction of oxidized lipids and hydroperoxides, and as such their deficiency contributes to impaired antioxidant capacity of HDL in ESRD patients. In addition, acquired LCAT deficiency in ESRD can contribute to reduction of HDL antioxidant capacity. This is because by hydrolysis of SN-2 fatty acids, LCAT removes oxidized fatty acids in oxidatively modified phospholipids, which could otherwise initiate/sustain oxidation-chain reaction and exert proinflammatory and platelet-activating factor-like activity. The ESRD group showed a marked reduction of HDL anti-inflammatory activity as evidenced by impaired HDL-mediated inhibition of LDL-induced monocyte chemotactic activity. The observed defect cannot be attributed to low plasma HDL level in the ESRD group, as equal amounts of isolated HDL were used in these in vitro experiments. Consequently, the observed HDL dysfunction must be due, primarily to qualitative abnormalities. Systemic inflammation has been shown to lower antioxidant and anti-inflammatory activity of HDL and transform HDL to a pro-oxidant, proinflammatory agent known as acute-phase HDL.24.Yu R. Yekta B. Vakili L. et al.Proatherogenic high- density lipoprotein, vascular inflammation, and mimetic peptides.Curr Atheroscler Rep. 2008; 10: 171-176Crossref PubMed Scopus (26) Google Scholar, 25.Haque S. Mirjafari H. Bruce I.N. Atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus.Curr Opin Lipidol. 2008; 19: 338-343Crossref PubMed Scopus (34) Google Scholar, 26.Ansell B.J. Fonarow G.C. Fogelman A.M. The paradox of dysfunctional high-density lipoprotein.Curr Opin Lipidol. 2007; 18: 427-434Crossref PubMed Scopus (162) Google Scholar Oxidative stress and inflammation are nearly constant features of advanced CKD,6.Vaziri N.D. Oxidative stress in chronic renal failure: The nature, mechanism and consequences.Semin Nephrol. 2004; 24: 469-473Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar, 8.Himmelfarb J. Stenvinkel P. Ikizler T.A. et al.The elephant in uremia: Oxidant stress as a unifying concept of cardiovascular disease in uremia.Kidney Int. 2002; 62: 1524-1538Abstract Full Text Full Text PDF PubMed Scopus (946) Google Scholar, 9.McCullough P.A. Why is chronic kidney disease the ‘spoiler’ for cardiovascular outcomes?.J Am Coll Cardiol. 2003; 41: 725-728Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 10.Stenvinkel P. Alvestrand A. Inflammation in end-stage renal disease: Sources, consequences, and therapy.Semin Dial. 2002; 15: 329-337Crossref PubMed Scopus (319) Google Scholar as evidenced by increased levels of inflammatory mediators (IL-6, IL-8, and tumor necrosis factor-α) and markers of oxidative stress (Protein carbonyls and MDA) in the ESRD patients used here. The prevailing inflammatory state likely contributes to the observed reduction of HDL anti-inflammatory function in the ESRD population. This could lead to a vicious cycle in which the underlying inflammation and oxidative stress induce HDL dysfunction and are aggravated by it. In addition to uptake of surplus cholesterol, HDL removes intact and oxidized phospholipids from the macrophages and resident cells in the artery wall.53.Guarnieri G.F. Moracchiello M. Campanacci L. et al.Lecithin-cholesterol acyltransferase (LCAT) activity in chronic uremia.Kidney Int Suppl. 1978; 8: S26-S30PubMed Google Scholar,54.Boadu E. Bilbey N.J. Francis G.A. Cellular cholesterol substrate pools for adenosine-triphosphate cassette transporter A1-dependent high-density lipoprotein formation.Curr Opin Lipidol. 2008; 19: 270-276Crossref PubMed Scopus (21) Google Scholar Consequently, HDL carries the bulk of oxidized phospholipids and lipoperoxides in the plasma55.Bowry V.W. Stanley K.K. Stocker R. 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