Decreased clearance of uraemic and mildly carbamylated low‐density lipoprotein

Hörkkö, Sohvi; Huttunen, K; Kervinen, Kari; Kesäniemi, Y. Antero

doi:10.1111/j.1365-2362.1994.tb00974.x

Cited by 59 publications

(31 citation statements)

References 36 publications

(12 reference statements)

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“…31 In addition, LDL isolated from uremic patients and uremic mouse aortic plaque have an enhanced degree of carbamylation and possess multiple proatherogenic biologic properties on in vitro testing. 7,10,13,34 However, ESRD, like CVD, has become increasingly recognized as a systemic inflammatory disease. 17,29,30,36,37 MPO, an abundant granulocyte protein, is a known mediator of vascular inflammation and plaque vulnerability and has been mechanistically linked to almost all stages of CVD, including culprit lesions (i.e., at sites of atherosclerotic plaque rupture and intracoronary thrombus).…”

Section: Discussionmentioning

confidence: 99%

“…13 Further evidence supporting a potential mechanistic link between protein carbamylation and the pathogenesis of atherosclerosis comes from reports that uremic or carbamylated LDL induces vascular endothelial cell apoptosis, has decreased recognition by the LDL receptor, and is recognized by macrophage scavenger receptor class A. 7,13 On the basis of the preceding observations, we hypothesized that PBHCit may have potential clinical utility in riskstratifying patients with kidney disease, a high-risk cohort in whom traditional risk factors do not adequately identify incident cardiovascular risks. We now report results examining the relationship between systemic levels of PBHCit and incident mortality risks in patients undergoing maintenance hemodialysis (MHD).…”

mentioning

confidence: 99%

“…5 The complex pathophysiology associated with ESRD and chronic uremia has been hypothesized to be mediated, in part, through posttranslational modification of proteins by carbamylation. [6][7][8][9][10][11][12][13] Urea, a byproduct of protein metabolism, is in equilibrium with an electrophilic pair of species, the cyanate ↔ isocyanate couple, which can react with nucleophilic amino acid side groups, such as the «-amino moiety of lysine, resulting in posttranslational modification of proteins [13][14][15] (Figure 1). Proteins purified from patients with chronic uremia have demonstrated dysfunction associated with the degree of carbamylation.…”

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confidence: 99%

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Protein Carbamylation Predicts Mortality in ESRD

Koeth¹,

Kalantar-Zadeh

Wang³

et al. 2013

Journal of the American Society of Nephrology

127

125

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Traditional risk factors fail to explain the increased risk for cardiovascular morbidity and mortality in ESRD. Cyanate, a reactive electrophilic species in equilibrium with urea, posttranslationally modifies proteins through a process called carbamylation, which promotes atherosclerosis. The plasma level of proteinbound homocitrulline (PBHCit), which results from carbamylation, predicts major adverse cardiac events in patients with normal renal function, but whether this relationship is similar in ESRD is unknown. We quantified serum PBHCit in a cohort of 347 patients undergoing maintenance hemodialysis with 5 years of follow-up. Kaplan-Meier analyses revealed a significant association between elevated PBHCit and death (log-rank P,0.01). After adjustment for patient characteristics, laboratory values, and comorbid conditions, the risk for death among patients with PBHCit values in the highest tertile was more than double the risk among patients with values in the middle tertile (adjusted hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.5-3.9) or the lowest tertile (adjusted HR, 2.3; 95% CI, 1.5-3.7). Including PBHCit significantly improved the multivariable model, with a net reclassification index of 14% (P,0.01). In summary, seurm PBHCit, a footprint of protein carbamylation, predicts increased cardiovascular risk in patients with ESRD, supporting a mechanistic link among uremia, inflammation, and atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Protein Carbamylation Predicts Mortality in ESRD

Koeth¹,

Kalantar-Zadeh

Wang³

et al. 2013

Journal of the American Society of Nephrology

127

125

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“…• Atherosclerosis is increased in the presence of carbamylated low-density lipoprotein (LDL) which induces vascular endothelial cell apoptosis; carbamylation of LDL also decreases its recognition by the LDL receptor but increases uptake by macrophage scavenger receptor class A [33,92,93]. Carbamylated LDL also increases the adhesion of monocytes to endothelial cells through enhanced vascular cell adhesion protein-1, CD106 (VCAM-1) and intercellular adhesion molecule-1, CD54 (ICAM-1) expression [94], and induces proliferation of vascular smooth muscle cells [93].…”

Section: Sh Amino Acid Protein Lysylmentioning

confidence: 99%

Urea, a true uremic toxin: the empire strikes back

Lau

Vaziri

2016

Clinical Science

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Blood levels of urea rise with progressive decline in kidney function. Older studies examining acute urea infusion suggested that urea was well-tolerated at levels 8-10× above normal values. More recent in vitro and in vivo work argue the opposite and demonstrate both direct and indirect toxicities of urea, which probably promote the premature aging phenotype that is pervasive in chronic kidney disease (CKD). Elevated urea at concentrations typically encountered in uremic patients induces disintegration of the gut epithelial barrier, leading to translocation of bacterial toxins into the bloodstream and systemic inflammation. Urea induces apoptosis of vascular smooth muscle cells as well as endothelial dysfunction, thus directly promoting cardiovascular disease. Further, urea stimulates oxidative stress and dysfunction in adipocytes, leading to insulin resistance. Finally, there are widespread indirect effects of elevated urea as a result of the carbamylation reaction, where isocyanic acid (a product of urea catabolism) alters the structure and function of proteins in the body. Carbamylation has been linked with renal fibrosis, atherosclerosis and anaemia. In summary, urea is a re-emerging Dark Force in CKD pathophysiology. Trials examining low protein diet to minimize accumulation of urea and other toxins suggest a clinical benefit in terms of slowing progression of CKD.

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“…Cyanate subsequently reacts irreversibly with the N-terminal groups of amino acids, peptides and many proteins by a process known as carbamylation (2)(3)(4). Accordingly, the potential role of cyanate and carbamylation has to date been investigated only in the context of uremia (2,(5)(6)(7). Proteins isolated from patients with chronic renal failure and end-stage renal disease have been shown to be easily carbamylated due to the urea-derived high concentrations of cyanate.…”

Section: Introductionmentioning

confidence: 99%

Cyanate attenuates insulin secretion in cultured pancreatic β cells

2012

Mol Med Report

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Abstract. The vast majority of long-term complications in transplanted patients are associated with cardiovascular disease. Previously, an alternative and dominant mechanism for cyanate formation in atherosclerotic lesions has been discovered. This study was designed to determine the effect of cyanate on insulin secretion in cultured pancreatic β cells (INS-1 cells). The cytotoxicity of cyanate was determined by 3-(4,5-Desethyithiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Insulin secretion was measured by ELISA in cyanatetreated INS-1 cells. Reactive oxygen species (ROS) generation was also determined by measuring the fluorescent oxidized product of 2,7-dichlorefluorescein in cyanate-treated INS-1 cells. FACS analysis was carried out to determine the effect of cyanate on the apoptosis of INS-1 cells. Firstly, we found that cyanate, within concentration ranges in which no cytotoxic effect was observed (0.01, 0.1 and 1.0 mM), decreased insulin secretion dose-dependently in both non-glucose-stimulated and glucose-stimulated INS-1 cells. Cyanate at a 1.0 mM concentration inhibited insulin secretion by more than 50% in non-glucose-stimulated cells and glucose (5 and 10 mM)-stimulated cells. Cyanate, however, did not affect ROS generation. Furthermore, no pro-or anti-apoptotic effect was observed in cyanate-treated INS-1 cells. The results in this study suggest the possible inhibitory effect of cyanate on insulin secretion in INS-1 pancreatic β cells. The inhibitory effect was not mediated either by ROS generation or by apoptosis. Further studies to determine the underlying mechanisms will be of benefit.

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Decreased clearance of uraemic and mildly carbamylated low‐density lipoprotein

Cited by 59 publications

References 36 publications

Protein Carbamylation Predicts Mortality in ESRD

Protein Carbamylation Predicts Mortality in ESRD

Urea, a true uremic toxin: the empire strikes back

Cyanate attenuates insulin secretion in cultured pancreatic β cells

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