Nonenzymatic Glycation Impairs the Antiinflammatory Properties of Apolipoprotein A-I
Objective— The goal of this study was to investigate the effects of nonenzymatic glycation on the antiinflammatory properties of apolipoprotein (apo) A-I.
Methods and Results— Rabbits were infused with saline, lipid-free apoA-I from normal subjects (apoA-IN), lipid-free apoA-I nonenzymatically glycated by incubation with methylglyoxal (apoA-IGlyc in vitro), nonenzymatically glycated lipid-free apoA-I from subjects with diabetes (apoA-IGlyc in vivo), discoidal reconstituted high-density lipoproteins (rHDL) containing phosphatidylcholine and apoA-IN, (A-IN)rHDL, or apoA-IGlyc in vitro, (A-IGlyc in vitro)rHDL. At 24 hours postinfusion, acute vascular inflammation was induced by inserting a nonocclusive, periarterial carotid collar. The animals were euthanized 24 hours after the insertion of the collar. The collars caused intima/media neutrophil infiltration and increased endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). ApoA-IN infusion decreased neutrophil infiltration and VCAM-1 and ICAM-1 expression by 89%, 90%, and 66%, respectively. The apoA-IGlyc in vitro infusion decreased neutrophil infiltration by 53% but did not reduce VCAM-1 or ICAM-1 expression. ApoA-IGlyc in vivo did not inhibit neutrophil infiltration or adhesion molecule expression. (A-IGlyc in vitro)rHDL also inhibited vascular inflammation less effectively than (A-IN)rHDL. The reduced antiinflammatory properties of nonenzymatically glycated apoA-I were attributed to a reduced ability to inhibit nuclear factor-κB activation and reactive oxygen species formation.
Conclusion— Nonenzymatic glycation impairs the antiinflammatory properties of apoA-I.
The ability of high-density lipoproteins (HDL) to inhibit inflammation in vitro is well recognized. Work from this and other laboratories has shown that HDL from human plasma and discoidal reconstituted HDL containing phosphatidylcholine and apolipoprotein (apo) A-I, (A-I)rHDL, inhibit intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) expression in activated, cultured human umbilical vein endothelial cells.1,2 Discoidal (A-I)rHDL also inhibit inflammation in vivo by reducing E-selectin expression in a porcine model of acute cutaneous inflammation.3 Discoidal (A-I)rHDL also improve renal function, reduce renal injury, decrease renal leukocyte infiltration, and decrease ICAM-1 and P-selectin expression in a rat model of ischemia/reperfusion injury.4
Recent work from this laboratory has shown that discoidal (A-I)rHDL prevent the acute vascular inflammation that results from the placement of nonocclusive periarterial collars around rabbit carotid arteries.5 In that study, 3 daily infusions of either discoidal (A-I)rHDL, lipid-free apoA-I, or small phosphatidylcholine-containing unilamellar vesicles markedly reduced inflammation in the collared arteries, as evidenced by decreased intima/media neutrophil infiltration and reduced endothelial expression of VCAM-1, ICAM-1, and monocyte chemoattractant protein-1.5 A follow-up study established that comparable antiinflammatory effects were mediated by a single apoA-I infusion administered 24 hours before collar insertion or at the time of collar insertion.6
Both type 1 diabetes and type 2 diabetes are associated with subclinical inflammation and modestly elevated plasma levels of inflammatory markers such as C-reactive protein, soluble ICAM-1, and soluble VCAM-1.7–9 Proinflammatory cytokines, interleukin-6, interleukin-1β, and tumor necrosis factor-α levels are also elevated in subjects with diabetes.10 Under conditions of chronic hyperglycemia, as are frequently observed in poorly controlled diabetes, plasma proteins and apolipoproteins, such as apoA-I, may become nonenzymatically glycated.11,12 Although these modifications are usually attributed to persistently elevated blood glucose levels, it is noteworthy that glucose mediates these changes very slowly.13 However, highly reactive glucose-derived dicarbonyl compounds, such as methylglyoxal (MG), glycoaldehyde, and 3-deoxyglucosone, nonenzymatically glycate plasma proteins and apolipoproteins at a rapid rate.14 This causes extensive cross-linking and irreversible conversion of the modified proteins into advanced glycation end products (AGEs), which are ligands for the endothelial advanced glycation end product receptor, RAGE.15,16 The binding of AGEs to RAGE activates the endothelium, increases VCAM-1, ICAM-1, and E-selectin expression,17,18 and exacerbates diabetes-associated inflammation. These findings, together with the observation that hyperglycemia can alter HDL function,19 raise the possibility that nonenzymatic glycation may reduce the antiinflammatory properties of apoA-I.
We have addressed this question by comparing lipid-free apoA-I from normal subjects (apoA-IN), lipid-free apoA-IN that has been nonenzymatically glycated in vitro by incubation with MG (apoA-IGlyc in vitro), and lipid-free apoA-I from subjects with type 2 diabetes and microvascular complications (apoA-IGlyc in vivo) in terms of their ability to inhibit acute vascular inflammation in collared carotid arteries of normocholesterolemic New Zealand white (NZW) rabbits. The results establish that apoA-IGlyc in vitro and apoA-IGlyc in vivo inhibit acute vascular inflammation less effectively than apoA-IN. In the case of apoA-IGlyc in vitro, these adverse effects were apparent irrespective of whether it was administered in a lipid-free form or as a component of discoidal rHDL. These reduced antiinflammatory properties of nonenzymatically glycated apoA-I were associated with enhanced phosphorylation of the inhibitor of κB, IκBα; reduced inhibition of nuclear translocation of nuclear factor-κB (NF-κB); and a reduced ability to inhibit reactive oxygen species (ROS) formation.
For the in vivo arm of the study, single infusions of apoA-IN or apoA-IGlyc in vitro in the lipid-free form or as a constituent of discoidal reconstituted high density lipoproteins (rHDL) containing phosphatidylcholine, or lipid-free apoA-IGlyc in vivo, were administered to normocholesterolemic NZW rabbits 24 hours before insertion of a nonocclusive periarterial carotid collar. The animals were euthanized 24 hours after the insertion of the collar. Inflammation was assessed immunohistochemically as endothelial expression of ICAM-1 and VCAM-1 and intima/media neutrophil infiltration. For the in vitro studies, (A-IN)rHDL and (A-IGlyc in vitro) rHDL were incubated with cytokine-activated human coronary artery endothelial cells (HCAECs). VCAM-1 and ICAM-1 protein expression was quantified by flow cytometry. mRNA levels were determined by real-time polymerase chain reaction. Phosphorylation of IκBα and NF-κB nuclear translocation were assessed by Western blotting. ROS formation was assessed by incubation with dihydroethidium (DHE). Details are in the supplementary material, available online at http://atvb.ahajournals.org.
Characterization of Lipid-Free ApoA-IN, Lipid-Free ApoA-IGlyc in vitro, Lipid-Free ApoA-IGlyc in vivo, Discoidal (A-IN)rHDL, and Discoidal (A-IGlyc in vitro)rHDL
The (A-IN)rHDL consisted of a major population of particles (diameter, 12.5 nm) and 2 minor populations of particles, 14.3 and 8.5 nm in diameter. Incubation with MG did not affect discoidal (A-I)rHDL stoichiometry, but it reduced their diameters to 14.0, 10.7, and 8.3 nm (not shown). As judged by SDS-PAGE, cross-linking was evident in the apoA-IGlyc in vitro (supplementary Figure I) and the discoidal (A-IGlyc in vitro)rHDL (not shown).20,21 The apoA-IGlyc in vivo from subjects with type 2 diabetes (HbA1c, 7.0%±0.4%; total cholesterol, 3.1±0.5 mmol/L; triglycerides, 1.7±0.3 mmol/L; HDL cholesterol, 0.9±0.1 mmol/L) was not cross-linked and migrated to the same position as lipid-free apoA-IN (supplementary Figure I).
Compared with lipid-free A-IN and discoidal (A-IN)rHDL that were incubated in the absence of MG, incubation with MG modified approximately 40% of the arginine residues, 25% of the lysine residues, and 15% of the tryptophan residues in the lipid-free apoA-IGlyc in vitro and discoidal (A-IGlyc in vitro)rHDL (P<0.05) (supplementary Table I). The arginine, lysine, and tryptophan residues in the lipid-free apoA-IGlyc in vivo were not modified significantly.
Incubation with MG increased lipid-free apoA-I Nε-carboxymethyllysine (CML) levels from 6.0±0.7 to 11.0±2.8 pmol/mg protein (P<0.05) and Nε-carboxyethyllysine (CEL) levels from 2.9±0.7 to 51.7±15.4 pmol/mg protein (P<0.01). Lipid-free apoA-IGlyc in vivo Nε-carboxymethyllysine and Nε-carboxyethyllysine levels were 10.0±1.4 pmol/mg protein (P<0.05 versus lipid-free apoA-IN) and 13.0±0.3 pmol/mg protein (P<0.0001 versus lipid-free apoA-IN), respectively. Lipid-free apoA-IN (2S)-2-amino-5-(2-amino-5-methyl-4-oxo-4,5-dihydro-imidazol-1-yl)-pentanoic acid (MG-H2) levels were 39.2±1.5 pmol/mg protein, compared with 7306.0±46.5 pmol/mg protein for lipid-free apoA-IGlyc in vitro (P<0.0001) and 50.2±1.6 pmol/mg protein for lipid-free apoA-IGlyc in vivo (P<0.01).
The effects of nonenzymatic glycation on the conformation of apoA-I were assessed by surface plasmon resonance. Nonenzymatic glycation altered the conformation of the epitope recognized by monoclonal antibody AI-1.2 in the N-terminal domain of apoA-IGlyc in vivo (supplementary Figure II, white bars). The conformation of the central epitope recognized by monoclonal antibody AI-115.1 was also altered in apoA-IGlyc in vitro (black bars) and apoA-IGlyc in vivo (white bars). The conformation of the epitopes in the central region of apoA-IGlyc in vitro, to which monoclonal antibody AI-17 binds, and in the C-terminal domain, to which monoclonal antibody AI-141.7 binds, was also significantly modified (supplementary Figure II).
Effect of Nonenzymatically Glycated apoA-I on Neutrophil Infiltration into Collared Carotid Arteries
Preinfusion plasma concentrations of total cholesterol, HDL cholesterol, and rabbit apoA-I were 1.05±0.09 mmol/L, 0.63±0.29 mmol/L, and 0.78±0.04 mg/mL, respectively. At euthanization, the total cholesterol and HDL cholesterol concentrations were 1.29±0.11 and 0.64±0.24 mmol/L, respectively. ApoA-I levels could not be determined on the samples obtained at euthanization because the antirabbit apoA-I antibody partly cross-reacted with human apoA-I. However, the results of an earlier study in which rabbits were infused with 8 mg/kg rabbit apoA-I established that this intervention leads to only a modest and transient increase in plasma apoA-I levels.5
Compared with what was observed for the noncollared arteries (Figure 1A), extensive infiltration of CD18+ cells was apparent in the intima/media of the collared arteries from the saline-infused animals (Figure 1B). These neutrophils were most likely recruited from the vessel lumen. However, the possibility that some neutrophils may also have been recruited via the adventitia cannot be excluded. The absence of cells staining positive for RAM11 and CD43 confirmed that these cells were not macrophages or lymphocytes (not shown). The lipid-free apoA-IN infusion decreased neutrophil infiltration into the artery wall from 8.7±0.4 to 1.0±0.2 image units (Figure 1C) (P<0.0001). Infusion of lipid-free apoA-IGlyc in vitro (Figure 1E) decreased neutrophil infiltration from 8.7±0.4 to 4.1±0.1 image units (P<0.0001). This inhibition was less than that mediated by unmodified, lipid-free apoA-IN (P<0.001). Lipid-free apoA-IGlyc in vivo did not inhibit neutrophil infiltration into the collared arteries (Figure 1G).
The discoidal (A-IN)rHDL infusion decreased neutrophil infiltration into the collared arteries from 8.7±0.4 (saline-infused animals) to 2.0±0.3 image units (P<0.0001). The discoidal (A-IGlyc in vitro)rHDL (Figure 1F) decreased neutrophil infiltration from 8.7±0.4 to 4.1±0.8 image units (P<0.001) and therefore inhibited neutrophil infiltration into the collared arteries less effectively than the discoidal (A-IN)rHDL (Figure 1D) (P<0.05).
Effect of Nonenzymatically Glycated ApoA-I on ICAM-1 Expression in Collared Carotid Arteries
The carotid collars markedly increased endothelial ICAM-1 expression in the saline-infused animals (Figure 2A versus 2B). The lipid-free apoA-IN infusion decreased ICAM-1 expression from 12.1±0.3 to 4.1±0.4 image units (P<0.0001) (Figure 2C). Neither lipid-free apoA-IGlyc in vitro (Figure 2E) nor apoA-IGlyc in vivo (Figure 2G) decreased ICAM-1 expression. Relative to the saline-infused animals, the discoidal (A-IN)rHDL decreased ICAM-1 expression from 12.0±0.3 to 5.2±0.7 image units (P<0.01) (Figure 2D). The discoidal (A-IGlyc in vitro)rHDL did not inhibit ICAM-1 expression (Figure 2F).
Effect of Nonenzymatically Glycated ApoA-I on VCAM-1 Expression in Collared Carotid Arteries
As reported previously and confirmed here, carotid collars increase endothelial expression of VCAM-1 (Figure 3A versus 3B).5,6 Infusion of lipid-free apoA-IN reduced VCAM-1 expression from 17.2±0.6 to 1.8±0.1 image units (P<0.0001) (Figure 3C). Lipid-free apoA-IGlyc in vitro (Figure 3E) and lipid-free apoA-IGlyc in vivo (Figure 3G) did not inhibit VCAM-1 expression.
The discoidal (A-IN)rHDL decreased VCAM-1 expression from 17.2±0.6 to 2.0±0.2 image units (P<0.0001), whereas the discoidal (A-IGlyc in vitro)rHDL reduced VCAM-1 expression to 9.0±0.6 image units (P<0.01). The discoidal (A-IGlyc in vitro)rHDL (Figure 3F) therefore inhibited VCAM-1 expression less effectively than discoidal (A-IN)rHDL (Figure 3D) (P<0.0001).
Effect of Nonenzymatically Glycated apoA-I on ICAM-1 and VCAM-1 Expression in HCAECs
Experiments were carried out to determine whether nonenzymatically glycated apoA-I inhibits inflammation less effectively than apoA-IN in cultured HCAECs (Figure 4). Discoidal rHDL were used for this study because lipid-free apoA-I does not inhibit inflammation in cultured endothelial cells.1
Stimulation of HCAECs with tumor necrosis factor-α (TNF-α) significantly increased ICAM-1 and VCAM-1 protein expression (Figure 4). Preincubation with discoidal (A-IN)rHDL (final apoA-I concentration, 0.5 mg/mL) reduced ICAM-1 expression from 4.0±0.2 to 2.8±0.1 U (P<0.01) and VCAM-1 expression from 3.9±0.2 to 2.5±0.2 U (P<0.01). Comparable results were obtained at a final apoA-I concentration of 1.0 mg/mL, where preincubation with (A-IGlyc in vitro)rHDL reduced ICAM-1 expression from 4.0±0.2 to 3.3±0.2 and VCAM-1 expression from 3.9±0.2 to 3.2±0.1 arbitrary units (P<0.05 for both versus TNF-α only). The (A-IGlyc in vitro)rHDL did not significantly inhibit adhesion molecule expression at a final apoA-I concentration of 0.5 mg/mL. Overall, the (A-IGlyc in vitro)rHDL inhibited VCAM-1 and ICAM-1 expression less effectively than (A-IN)rHDL (P<0.05).
Effect of Nonenzymatically Glycated ApoA-I on IκBα Phosphorylation and NF-κB Nuclear Translocation
Phosphorylation of IκBα disrupts the inactive cytosolic NF-κB/IκB complex, causing NF-κB to translocate to the nucleus, where it binds to promoter regions in the ICAM-1 and VCAM-1 genes and increases their expression (Figure 5). As discoidal (A-IN)rHDL inhibit IκBα phosphorylation and NF-κB nuclear translocation,22 we examined whether the attenuated antiinflammatory properties of (A-IGlyc in vitro)rHDL could be due to reduced inhibition of IκBα phosphorylation and NF-κB nuclear translocation.
Stimulation of HCAECs with TNF-α increased the phosphorylated-IκBα/IκBα ratio and nuclear NF-κB p65 subunit levels. Preincubation with (A-IN)rHDL reduced the phosphorylated IκBα/IκBα ratio by 55% (from 293.6±50.5 to 132.1±6.4 U) and nuclear NF-κB p65 subunit levels by 38% (from 356.9±47.2 to 220.7±14.5 U) (P<0.05 for both). Preincubation with (A-IGlyc in vitro)rHDL did not significantly reduce IκBα phosphorylation or nuclear translocation of the NF-κB p65 subunit (P<0.05 versus (A-IN)rHDL).
Effect of Nonenzymatically Glycated ApoA-I on ROS Production In Vitro and In Vivo
We have reported previously that (A-IN)rHDL infusions inhibit ROS production in collared NZW rabbit carotid arteries (Figure 6).5,22 To ascertain whether (A-IGlyc in vivo)rHDL inhibits ROS production less effectively than (A-IN)rHDL, collared carotid artery sections were incubated with DHE. In the presence of superoxide, DHE is oxidized to products that fluoresce when they intercalate into DNA. The carotid collars mediated robust formation of DHE-derived oxidation products (Figure 6A). A single (A-IN)rHDL infusion reduced the collar-mediated fluorescent oxidation product formation by 51%, from 11.9±0.9 to 5.8±0.3 U (P<0.05). (A-IGlyc in vivo)rHDL did not decrease collar-mediated formation of DHE-derived fluorescent oxidation products (P<0.05 versus (A-IN)rHDL) (Figure 6A).
This result was recapitulated in cultured HCAECs, in which preincubation with (A-IN)rHDL and (A-IGlyc in vitro)rHDL reduced the TNF-α-mediated formation of fluorescent products from 17.8±0.8 to 11.4±1.0 (P<0.01) and 14.8±1.2 (P<0.05) arbitrary units, respectively (Figure 6B). (A-IN)rHDL inhibited DHE-derived fluorescent oxidation product formation more effectively than (A-IGlyc in vitro)rHDL did (P<0.05) (Figure 6B).
We have previously reported that implantation of nonocclusive silastic collars around carotid arteries in normocholesterolemic rabbits induces an acute inflammatory response that causes infiltration of neutrophils into the intima/media and increases endothelial expression of VCAM-1 and ICAM-1.5,6 Both the neutrophil infiltration and adhesion molecule expression are markedly decreased when small amounts of apoA-I, either in the lipid-free form or as a constituent of discoidal (A-I)rHDL, are infused into the animals before collar insertion. The present study shows that these antiinflammatory properties of lipid-free apoA-I and discoidal (A-I)rHDL are markedly reduced if the animals are infused with apoA-I that has been nonenzymatically glycated by incubation in vitro with MG or modified in vivo as a consequence of the persistent hyperglycemia that can occur in type 2 diabetes.
Although the modifications that were sustained when apoA-I was nonenzymatically glycated by incubation with MG differed from those observed for apoA-I from subjects with type 2 diabetes (supplementary Table I), both preparations displayed similar reductions in their antiinflammatory properties. This is consistent with the proposition that in vivo glycation of apoA-I in people with diabetes may compromise HDL functionality and increase cardiovascular risk.
There are several possible explanations for the increased cardiovascular risk in people with type 2 diabetes. One relates to the prevalence of diabetic dyslipidemia, which is characterized by elevated plasma triglycerides; a low-density lipoprotein fraction containing potentially proatherogenic small, dense particles; and low HDL cholesterol levels. The HDL in these individuals also tend to be smaller, triglyceride-enriched, and more dense than normal. Recent reports have established that triglyceride enrichment can compromise the functionality of HDL.23–25 The current study extends these observations by showing that the nonenzymatic glycation of apoA-I, which is known to occur in diabetes, may further compromise HDL functionality.
A possible explanation for the reduced antiinflammatory properties of nonenzymatically glycated apoA-I may be that it is cleared from the circulation more rapidly than normal apoA-I. However, a recent study carried out in this laboratory, in which normocholesterolemic NZW rabbits received a single 8 mg/kg infusion of 125I-labeled lipid-free apoA-IN, indicated that this is unlikely to be the case. Those results showed that <10% of the radiolabel remained in the circulation at 3 hours postinfusion (Patel and Rye, unpublished, 2009). Thus, even if nonenzymatically glycated apoA-I was catabolized more rapidly than apoA-IN, both preparations would have been cleared from the circulation long before carotid collar insertion. This suggests that rather than having a direct, physical effect on the artery wall, the antiinflammatory properties of apoA-I may reflect altered gene transcription and the inhibition of one or more key intracellular inflammation signaling pathways.
The reduction in VCAM-1 expression following administration of apoA-IN is consistent with reduced activation of NF-κB, a key inflammatory mediator, and the primary regulator of VCAM-1 gene transcription.22,26–29 ApoA-IN, by contrast, inhibited ICAM-1 gene expression to a lesser extent than VCAM-1. This is most likely because ICAM-1 is regulated by several signaling pathways, only one of which involves NF-κB.30 The present results are therefore consistent with nonenzymatic glycation significantly compromising the ability of apoA-I to inhibit inflammation by directly inhibiting the NF-κB pathway (Figure 5).
The inhibition of VCAM-1 and ICAM-1 gene expression by lipid-free or lipid-associated apoA-I is most likely initiated by the binding of apoA-I to specific receptors or domains, such as lipid rafts, on the endothelial surface. The reduced antiinflammatory properties of nonenzymatically glycated apoA-I may therefore be a consequence of structural changes that prevent it from accessing these domains. Evidence that this could be the case comes from our current (supplementary Figure II) and earlier work showing that nonenzymatic glycation alters the conformation of the central and C-terminal domains of apoA-I.20,21 This may mask specific apoA-I binding sites and inhibit interactions with endothelial receptors and/or membrane domains that downregulate inflammatory signaling pathways.
The structural and conformational changes that occur when apoA-I is nonenzymatically glycated by MG in vitro are similar to what has been reported in vivo for AGE formation.14 It is also well established that AGEs that are generated in vivo, as well as proteins that are nonenzymatically glycated in vitro, are ligands for RAGE31 and that the binding of AGE to RAGE upregulates VCAM-1, and possibly ICAM-1, expression via activation of NF-κB.14,18,32,33 When taken together, these observations suggest that the structural changes that occur when apoA-I is nonenzymatically glycated may maintain VCAM-1 and ICAM-1 expression via enhanced binding to RAGE.
In summary, this study shows that nonenzymatic glycation adversely affects the antiinflammatory properties of apoA-I, irrespective of whether the modifications occur in vitro or in vivo. This finding is of considerable physiological significance given that subjects with type 2 diabetes, especially those with micro- and macrovascular complications, tend to be in a proinflammatory state. The current results highlight the importance of maintaining good glycemic control in such individuals, and they indicate that therapeutic intervention with cross-link breakers, which reportedly prevent protein modifications, have the potential to decrease the risk of the microvascular and possibly the macrovascular complications that accompany this increasingly prevalent disorder.
Sources of Funding
This work was supported by National Health and Medical Research Council of Australia Grant 222722.
Estelle Nobécourt and Fatiha Tabet contributed equally to this work.
Received on: March 3, 2009; final version accepted on: January 4, 2010.
Baker PW, Rye KA, Gamble JR, Vadas MA, Barter PJ. Ability of reconstituted high density lipoproteins to inhibit cytokine-induced expression of vascular cell adhesion molecule-1 in human umbilical vein endothelial cells. J Lipid Res. 1999; 40: 345–353.
Cockerill GW, Rye KA, Gamble JR, Vadas MA, Barter PJ. High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules. Arterioscler Thromb Vasc Biol. 1995; 15: 1987–1994.
Cockerill GW, Huehns TY, Weerasinghe A, Stocker C, Lerch PG, Miller NE, Haskard DO. Elevation of plasma high-density lipoprotein concentration reduces interleukin-1-induced expression of E-selectin in an in vivo model of acute inflammation. Circulation. 2001; 103: 108–112.
Thiemermann C, Patel NS, Kvale EO, Cockerill GW, Brown PA, Stewart KN, Cuzzocrea S, Britti D, Mota-Filipe H, Chatterjee PK. High density lipoprotein (HDL) reduces renal ischemia/reperfusion injury. J Am Soc Nephrol. 2003; 14: 1833–1843.
Nicholls SJ, Dusting GJ, Cutri B, Bao S, Drummond GR, Rye KA, Barter PJ. Reconstituted high-density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits. Circulation. 2005; 111: 1543–1550.
Schaumberg DA, Glynn RJ, Jenkins AJ, Lyons TJ, Rifai N, Manson JE, Ridker PM, Nathan DM. Effect of intensive glycemic control on levels of markers of inflammation in type 1 diabetes mellitus in the diabetes control and complications trial. Circulation. 2005; 111: 2446–2453.
Marfella R, Esposito K, Giunta R, Coppola G, De Angelis L, Farzati B, Paolisso G, Giugliano D. Circulating adhesion molecules in humans: role of hyperglycemia and hyperinsulinemia. Circulation. 2000; 101: 2247–2251.
Otsuki M, Hashimoto K, Morimoto Y, Kishimoto T, Kasayama S. Circulating vascular cell adhesion molecule-1 (VCAM-1) in atherosclerotic NIDDM patients. Diabetes. 1997; 46: 2096–2101.
Devaraj S, Glaser N, Griffen S, Wang-Polagruto J, Miguelino E, Jialal I. Increased monocytic activity and biomarkers of inflammation in patients with type 1 diabetes. Diabetes. 2006; 55: 774–779.
Curtiss LK, Witztum JL. Plasma apolipoproteins AI, AII, B, CI, and E are glucosylated in hyperglycemic diabetic subjects. Diabetes. 1985; 34: 452–461.
Thornalley PJ, Langborg A, Minhas HS. Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem J. 1999; 344: 109–116.
Bucala R, Makita Z, Vega G, Grundy S, Koschinsky T, Cerami A, Vlassara H. Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency. Proc Natl Acad Sci U S A. 1994; 91: 9441–9445.
Kislinger T, Fu C, Huber B, Qu W, Taguchi A, Du Yan S, Hofmann M, Yan SF, Pischetsrieder M, Stern D, Schmidt AM. N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem. 1999; 274: 31740–31749.
Schmidt AM, Hori O, Chen JX, Li JF, Crandall J, Zhang J, Cao R, Yan SD, Brett J, Stern D. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest. 1995; 96: 1395–1403.
Tabet F, Remaley AT, Segaliny AI, Millet J, Yan L, Nakhla S, Barter PJ, Rye KA, Lambert G. The 5A apolipoprotein A-I mimetic peptide displays antiinflammatory and antioxidant properties in vivo and in vitro. Arterioscler Thromb Vasc Biol. 2009. In press.
Patel S, Puranik R, Nakhla S, Lundman P, Stocker R, Wang XS, Lambert G, Rye KA, Barter PJ, Nicholls SJ, Celermajer DS. Acute hypertriglyceridaemia in humans increases the triglyceride content and decreases the anti-inflammatory capacity of high density lipoproteins. Atherosclerosis. 2008; 204: 424–428.
de Souza JA, Vindis C, Hansel B, Negre-Salvayre A, Therond P, Serrano CV, Jr., Chantepie S, Salvayre R, Bruckert E, Chapman MJ, Kontush A. Metabolic syndrome features small, apolipoprotein A-I-poor, triglyceride-rich HDL3 particles with defective anti-apoptotic activity. Atherosclerosis. 2008; 197: 84–94.
Shu HB, Agranoff AB, Nabel EG, Leung K, Duckett CS, Neish AS, Collins T, Nabel GJ. Differential regulation of vascular cell adhesion molecule 1 gene expression by specific NF-kappa B subunits in endothelial and epithelial cells. Mol Cell Biol. 1993; 13: 6283–6289.
Denk A, Goebeler M, Schmid S, Berberich I, Ritz O, Lindemann D, Ludwig S, Wirth T. Activation of NF-kappa B via the Ikappa B kinase complex is both essential and sufficient for proinflammatory gene expression in primary endothelial cells. J Biol Chem. 2001; 276: 28451–28458.
Weber C, Erl W, Pietsch A, Strobel M, Ziegler-Heitbrock HW, Weber PC. Antioxidants inhibit monocyte adhesion by suppressing nuclear factor-kappa B mobilization and induction of vascular cell adhesion molecule-1 in endothelial cells stimulated to generate radicals. Arterioscler Thromb. 1994; 14: 1665–1673.
Roebuck KA, Finnegan A. Regulation of intercellular adhesion molecule-1 (CD54) gene expression. J Leukoc Biol. 1999; 66: 876–888.
Collison KS, Parhar RS, Saleh SS, Meyer BF, Kwaasi AA, Hammami MM, Schmidt AM, Stern DM, Al-Mohanna FA. RAGE-mediated neutrophil dysfunction is evoked by advanced glycation end products (AGEs). J Leukoc Biol. 2002; 71: 433–444.