Chronic Uremia Stimulates LDL Carbamylation and Atherosclerosis

Apostolov, Eugene O.; Ray, Debarti; Savenka, Alena V.; Shah, Sudhir V.; Basnakian, Alexei G.

doi:10.1681/asn.2010040365

Cited by 109 publications

(104 citation statements)

References 27 publications

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“…The mechanisms at play for increased protein carbamylation within patients with ESRD are not known, but to some extent they are due to the chronic uremia associated with kidney dysfunction. 34 However, it is notable that the correlation between PBHCit and urea levels within the cohort, although significant, were relatively modest in magnitude (R=0.38) ( Table 2), indicating that only about 14% of the variation in PBHCit level could be explained by changes in urea level. The contribution of MPO to generation of PBHCit in this cohort is unclear.…”

Section: Discussionmentioning

confidence: 93%

“…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%

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Protein Carbamylation Predicts Mortality in ESRD

Koeth¹,

Kalantar-Zadeh

Wang³

et al. 2013

Journal of the American Society of Nephrology

124

121

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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: 93%

Section: Discussionmentioning

confidence: 99%

Protein Carbamylation Predicts Mortality in ESRD

Koeth¹,

Kalantar-Zadeh

Wang³

et al. 2013

Journal of the American Society of Nephrology

124

121

View full text Add to dashboard Cite

show abstract

“…The observation that oral administration of urea accelerates atherogenesis in non-uremic ApoE/mice fed with a high-fat diet in the absence of other factors and toxins that accumulate in CRF supported this hypothesis (13). Moreover, recent data demonstrated that the survival of patients on daily hemodialysis, which improves the removal of uremic toxins including urea, was 2-to 3-fold greater than that of patients dialyzed less frequently, and several recent in vitro and in vivo studies indicated a possible vascular toxicity of urea (14).…”

Section: Research Effectsmentioning

confidence: 81%

Vascular toxicity of urea, a new “old player” in the pathogenesis of chronic renal failure induced cardiovascular diseases

et al. 2018

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“…It is proposed that the generation of carbamyl-LDL is a common injurious event that links inflammation, smoking, and uremia as risk factors in atherogenesis [95]. Consequently levels of carbamyl-LDL in plasma are higher than levels of ox-LDL and in both uremic patients and in smokers levels are considerably higher [96,97]. The scavenger receptor LOX-1 receptor mainly recognise oxidised and carbamylated proteins as well as carbohydrate moieties.…”

Section: Ox-ldl In Cooperation With Risk Factors Becomes An Injuriousmentioning

confidence: 99%

“…When OSEs are detected simultaneously with these other epitopes, ox-LDLs become injurious particles that exacerbate endothelial damage [97,100]. This contributes to an uncontrolled entrance of modified and non-modified LDLs into the arterial intima where they are retained and oxidised, which alters their homeostasis and activates an immune response.…”

Section: Ox-ldl In Cooperation With Risk Factors Becomes An Injuriousmentioning

confidence: 99%

Are oxidised low-density lipoproteins the true inducers of inflammation in atherosclerosis?

Montero-Vega¹

2014

Inflammasome

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Low-density lipoproteins become oxidised (ox-LDL) when retained in the arterial intima and are considered to be the inducers of inflammation in atherosclerosis. Peroxidation of phospholipids generates a variety of oxidised molecules in LDL and leads to the formation of oxidised lipid-protein adducts. These oxidative modifications are the target of various pattern recognition receptors (PRRs) and constitute immunogenic neoepitopes, termed oxidation-specific epitopes (OSEs). OSEs are thought to be a class of danger-associated molecular patterns (DAMPs) that mediate pro-inflammatory signals in atherosclerosis. Nevertheless, identical OSEs are generated on apoptotic cells that are identified by innate immunity through the same receptors to promote housekeeping tasks and immunosuppression. The present study provides an alternative point of view and proposes that OSEs are ‘waste-associated molecular patterns’ (WAMPs) recognised by innate immunity as a signal for the presence of oxidised waste that must be cleared without triggering inflammation. The hypothesis presented here states that ox-LDL are not inflammatory per se but instead polarise macrophages for housekeeping functions; however, other immune alerts, which are generated under the influence of risk factors, cooperate with them in switching macrophage polarisation towards dangerous phenotypes that complicate atheromas with different tendencies. This hypothesis of ‘immune cooperation’ explains why atheromas grow silently for decades and reveals atherosclerosis to be a dynamic disease that begins with the retention and oxidation of LDL in the arterial intima and ends with the formation of a thrombus, but in which the underlying immune process changes over time and differs between patients.

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Chronic Uremia Stimulates LDL Carbamylation and Atherosclerosis

Cited by 109 publications

References 27 publications

Protein Carbamylation Predicts Mortality in ESRD

Protein Carbamylation Predicts Mortality in ESRD

Vascular toxicity of urea, a new “old player” in the pathogenesis of chronic renal failure induced cardiovascular diseases

Are oxidised low-density lipoproteins the true inducers of inflammation in atherosclerosis?

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