title: Carbamylated low-density lipoprotein induces oxidative stress and accelerated senescence in human endothelial progenitor cells.
abstract: Carbamylated low-density lipoprotein (cLDL) plays a role in atherosclerosis. In this study we evaluate the effect of uremia on LDL carbamylation and the effect of cLDL and oxidized LDL (oxLDL; 200 μg/ml) on number, function, and genomic stability of endothelial progenitor cells (EPCs) obtained from healthy volunteers. cLDL was generated after incubation of native LDL (nLDL) with uremic serum from patients with chronic kidney disease (CKD) stages 2-4. Oxidative stress was measured by flow cytometry and fluorescent microscopy, mitochondrial depolarization by flow cytometry, senescence by β-galactosidase activity and telomere length, and DNA damage by phosphorylated histone H2AX (γH2AX). The percentage of cLDL by uremic serum was related to the severity of CKD. Compared with nLDL, cLDL induced an increase in oxidative stress (62±5 vs. 8±3%, P<0.001) and cells with mitochondrial depolarization (73±7 vs. 9±5%, P<0.001), and a decrease in EPC proliferation and angiogenesis. cLDL also induced accelerated senescence (73±16 vs. 12±9%, P<0.001), which was associated with a decrease in the expression of γH2AX (62±9 vs. 5±3%, P<0.001). The degree of injury induced by cLDL was comparable to that observed with oxLDL. This study supports the hypothesis that cLDL triggers genomic damage in EPCs, resulting in premature senescence. We can, therefore, hypothesize that EPCs injury by cLDL contributes to an increase in atherosclerotic disease in CKD.
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba/Fundación de Investigaciones Biomédicas de Córdoba, Córdoba, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Carracedo
authors.forename: Ana
authors.initials: A
authors.lastname: Merino
authors.forename: Carolina
authors.initials: C
authors.lastname: Briceño
authors.forename: Sagrario
authors.initials: S
authors.lastname: Soriano
authors.forename: Paula
authors.initials: P
authors.lastname: Buendía
authors.forename: Laura
authors.initials: L
authors.lastname: Calleros
authors.forename: Mariano
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martín-Malo
authors.forename: Pedro
authors.initials: P
authors.lastname: Aljama
authors.forename: Rafael
authors.initials: R
authors.lastname: Ramírez
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D014511:Uremia / Q000503:physiopathology*
chemical_list: D008077:Lipoproteins, LDL; C039916:carbamyl-LDL; C099252:oxidized low density lipoprotein