Small-sized low-density lipoproteins of subclass B from patients with end-stage renal disease effectively augment tumor necrosis factor-α-induced adhesive properties in human endothelial cells

RationaleThe cardiovascular risk factor homocysteine is mainly bound to proteins in human plasma, and it has been hypothesized that homocysteinylated proteins are important mediators of the toxic effects of hyperhomocysteinemia. It has been recently demonstrated that homocysteinylated proteins are elevated in hemodialysis patients, a high cardiovascular risk population, and that homocysteinylated albumin shows altered properties.ObjectiveAim of this work was to investigate the effects of homocysteinylated albumin - the circulating form of this amino acid, utilized at the concentration present in uremia - on monocyte adhesion to a human endothelial cell culture monolayer and the relevant molecular changes induced at both cell levels.Methods and ResultsTreated endothelial cells showed a significant increase in monocyte adhesion. Endothelial cells showed after treatment a significant, specific and time-dependent increase in ICAM1 and VCAM1. Expression profiling and real time PCR, as well as protein analysis, showed an increase in the expression of genes encoding for chemokines/cytokines regulating the adhesion process and mediators of vascular remodeling (ADAM17, MCP1, and Hsp60). The mature form of ADAM17 was also increased as well as Tnf-α released in the cell medium. At monocyte level, treatment induced up-regulation of ICAM1, MCP1 and its receptor CCR2.ConclusionsTreatment with homocysteinylated albumin specifically increases monocyte adhesion to endothelial cells through up-regulation of effectors involved in vascular remodeling.

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“…Cell adhesion and endothelial damage are increased in uremia and paralleled by time-dependent VCAM-1 and ICAM-1 up-regulation [31], [32].…”

Section: Resultsmentioning

confidence: 99%

Homocysteinylated Albumin Promotes Increased Monocyte-Endothelial Cell Adhesion and Up-Regulation of MCP1, Hsp60 and ADAM17

et al. 2012

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“…Other pathophysiologic mechanisms also may play a role in increased sensitivity to chronic inflammation. For example, in individuals with ESRD, there is an increased prevalence of small-sized LDL subclass B, and these small-sized LDL particles sensitize vascular cells to inflammatory signals more than normal-sized LDL (40). Clearly, the pathophysiologic interrelationships between renal function, inflammation, and coronary events merit further study.…”

Section: Discussionmentioning

confidence: 99%

Kidney Dysfunction, Inflammation, and Coronary Events

Knight¹,

Rimm²,

Pai³

et al. 2004

Journal of the American Society of Nephrology

127

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Abstract. Kidney dysfunction and high C-reactive protein (CRP) levels are independently associated with coronary events. However, it is unclear whether the risk of coronary events associated with decreased kidney function is at least partially mediated by inflammation and whether the association between inflammatory biomarkers and coronary events is influenced by level of kidney function. With the use of a prospective, nested, case-control study design, the association among kidney function, inflammatory biomarker levels, and coronary events was studied. A total of 244 women who were participants in the Nurses' Health Study and had no history of cardiovascular disease received a diagnosis of an incident coronary event (defined as nonfatal myocardial infarction or death as a result of coronary disease) during the follow-up period from 1990 to 1998 and were matched to 486 control subjects. Serum creatinine and inflammatory biomarker levels were measured in blood samples collected in 1989. Creatinine clearance (CrCl) was estimated using creatinine, age, weight, and height. In multivariate analyses, the odds ratio (OR) for a coronary event in women with an estimated CrCl Ͻ60 ml/min was 2.33 (95% confidence interval [CI], 1.01 to 5.38) compared with those with a CrCl Ն90 ml/min. When soluble tumor necrosis factor receptor (sTNFR) I and II levels were added into this model individually, the observed OR for women with CrCl Ͻ60 ml/min was attenuated. In analyses stratified by estimated CrCl, higher high-sensitivity CRP (hs-CRP), IL-6, and sTNFR I and II levels each were significantly associated with an increased odds of coronary events in women with an estimated CrCl Յ74 ml/min but not in women with an estimated CrCl Ն75 ml/min. The OR per 5-mg/L unit increase in hs-CRP was 1.68 (95% CI, 1.13 to 2.52) for women with an estimated CrCl Յ74 ml/min, compared with 1.23 (95% CI, 0.86 to 1.76) and 0.99 (95% CI, 0.76 to 1.29) for women with an estimated CrCl 75 to 89 and Ն90 ml/min, respectively (P ϭ 0.004 for interaction). In conclusion, kidney dysfunction is associated with an increased odds of coronary events, and inflammation, as assessed by higher sTNFR I and II levels, may mediate some of this risk. Higher inflammatory biomarkers levels, specifically, hs-CRP, IL-6, and sTNFR I and II, were significantly associated with coronary events only in women with reduced kidney function. These findings warrant further investigation in other populations.

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“…Advanced glycation end products [13] or oxidative stress could be implicated in this process. On the other hand, increased prevalence of lipid sub-fractions (although not assessed in the present study), such as small-sized LDL or oxidized LDL, in renal-failure subjects may predispose crucial cell types towards a more intense inflammatory – and atherogenic – response [14]; this latter possibility should not be excluded, particularly since recent studies showed a strong relation between inflammation and atherogenic modification of the main lipid fractions [15]. A genetic predisposition connecting lipid metabolism, inflammation and atherosclerosis, such as apolipoprotein-E polymorphisms, might also account for the more intense inflammatory response in HD patients [16].…”

Section: Discussionmentioning

confidence: 99%

Release of Interleukin-6 and Its Soluble Receptors by Activated Peripheral Blood Monocytes Is Elevated in Hypocholesterolemic Hemodialysis Patients

et al. 2005

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Background: A reverse association between cholesterol level and cardiovascular disease mortality is observed in hemodialysis (HD) patients; this paradoxical relationship may be explained by the coexistence of inflammation. Interleukin-6 (IL-6) is a central regulator of inflammation; its action is augmented by the soluble IL-6 receptor (sIL-6R) and inhibited by the soluble gp130 (sgp130). In order to investigate the potential association of inflammation with cholesterol levels in the HD population, release of soluble IL-6 components by peripheral blood mononuclear cells (PBMCs) was measured in two groups of HD patients with distinctly different lipid profile and in a control group. Methods: Twenty-two HD patients with low serum cholesterol (range 85–171 mg/dl), 23 HD patients with high cholesterol (189–342 mg/dl) and 21 normolipidemic non-renal failure subjects were enrolled in the study. IL-6, sIL-6R and sgp130 were measured by ELISA in the serum and in the supernatant collected from cell cultures of activated or resting PBMCs isolated from all three groups. Results: Serum IL-6 and sgp130 level was higher while sIL-6R was lower in both groups of HD patients compared to the control group. The ex-vivo release of the IL-6 and sgp130 by unstimulated PBMCs did not differ significantly between the three groups but that of the sIL-6R was higher in non-renal failure than in hypercholesterolemic HD subjects. Production of sIL-6R by stimulated PBMCs was higher in low-cholesterol HD patients (p < 0.001) and the same was valid for the sgp130 release (p = 0.034). Release of IL-6 by activated PBMCs was higher in the low-cholesterol compared to the high-cholesterol HD patients group (p = 0.011 for post hoc test). Major serum lipid fractions were inversely correlated to IL-6 and sIL-6R production from stimulated PBMCs in HD but not in non-renal failure subjects. Finally, release of the sgp130 by PBMCs was significantly reduced in 13 hypertriglyceridemic – and hypercholesterolemic – HD patients. Conclusion: Production of soluble components of a crucial pro-inflammatory and potentially atherogenic cytokine, namely the IL-6, by stimulated PBMCs appears to be inversely correlated with the serum cholesterol levels in HD patients.

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Small-sized low-density lipoproteins of subclass B from patients with end-stage renal disease effectively augment tumor necrosis factor-α-induced adhesive properties in human endothelial cells

Cited by 12 publications

References 45 publications

Homocysteinylated Albumin Promotes Increased Monocyte-Endothelial Cell Adhesion and Up-Regulation of MCP1, Hsp60 and ADAM17

Homocysteinylated Albumin Promotes Increased Monocyte-Endothelial Cell Adhesion and Up-Regulation of MCP1, Hsp60 and ADAM17

Kidney Dysfunction, Inflammation, and Coronary Events

Release of Interleukin-6 and Its Soluble Receptors by Activated Peripheral Blood Monocytes Is Elevated in Hypocholesterolemic Hemodialysis Patients

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