title: Carbamylated low-density lipoprotein induces endothelial dysfunction.
abstract: OBJECTIVE
  Cardiovascular events remain the leading cause of death in Western world. Atherosclerosis is the most common underlying complication driven by low-density lipoproteins (LDL) disturbing vascular integrity. Carbamylation of lysine residues, occurring primarily in the presence of chronic kidney disease (CKD), may affect functional properties of lipoproteins; however, its effect on endothelial function is unknown.
  
  
  RESULTS
  Low-density lipoprotein from healthy donors was isolated and carbamylated. Vascular reactivity after treatment with native LDL (nLDL) or carbamylated LDL (cLDL) was examined in organ chambers for isometric tension recording using aortic rings of wild-type or lectin-like-oxidized LDL receptor-1 (LOX-1) transgenic mice. Reactive oxygen species (ROS) and nitric oxide (NO) production were determined using electron spin resonance spectroscopy. The effect of LDL-carbamyl-lysine levels on cardiovascular outcomes was determined in patients with CKD during a median follow-up of 4.7 years. Carbamylated LDL impaired endothelium-dependent relaxation to acetylcholine or calcium-ionophore A23187, but not endothelium-independent relaxation to sodium nitroprusside. In contrast, nLDL had no effect. Carbamylated LDL enhanced aortic ROS production by activating NADPH-oxidase. Carbamylated LDL stimulated endothelial NO synthase (eNOS) uncoupling at least partially by promoting S-glutathionylation of eNOS. Carbamylated LDL-induced endothelial dysfunction was enhanced in LOX-1 transgenic mice. In patients with CKD, LDL-carbamyl-lysine levels were significant predictors for cardiovascular events and all-cause mortality.
  
  
  CONCLUSIONS
  Carbamylation of LDL induces endothelial dysfunction via LOX-1 activation and increased ROS production leading to eNOS uncoupling. This indicates a novel mechanism in the pathogenesis of atherosclerotic disease which may be pathogenic and prognostic in patients with CKD and high plasma levels of cLDL.
authors.affiliation: University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
authors.forename: Thimoteus
authors.initials: T
authors.lastname: Speer
authors.affiliation: University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
authors.forename: Frederick O
authors.initials: FO
authors.lastname: Owala
authors.affiliation: University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
authors.forename: Erik W
authors.initials: EW
authors.lastname: Holy
authors.affiliation: Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
authors.forename: Stephen
authors.initials: S
authors.lastname: Zewinger
authors.affiliation: Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
authors.forename: Felix L
authors.initials: FL
authors.lastname: Frenzel
authors.affiliation: University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Stähli
authors.affiliation: Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
authors.forename: Marjan
authors.initials: M
authors.lastname: Razavi
authors.affiliation: Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Triem
authors.affiliation: Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Cvija
authors.affiliation: Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Lucia
authors.initials: L
authors.lastname: Rohrer
authors.affiliation: Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Seiler
authors.affiliation: Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
authors.forename: Gunnar H
authors.initials: GH
authors.lastname: Heine
authors.affiliation: Department of Internal Medicine IV, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Jankowski
authors.affiliation: Department of Internal Medicine IV, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Jankowski
authors.affiliation: Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
authors.forename: Giovanni G
authors.initials: GG
authors.lastname: Camici
authors.affiliation: Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.affiliation: Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
authors.forename: Danilo
authors.initials: D
authors.lastname: Fliser
authors.affiliation: University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.affiliation: University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland felix.tanner@access.uzh.ch.
authors.forename: Felix C
authors.initials: FC
authors.lastname: Tanner
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000502:physiology; D002318:Cardiovascular Diseases / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064368:Healthy Volunteers; D006801:Humans; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000503:physiopathology; D051127:Scavenger Receptors, Class E / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; C495138:Olr1 protein, mouse; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D014665:Vasodilator Agents; C039916:carbamyl-LDL; C007517:diphenyleneiodonium; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine
keywords: Carbamylation; Endothelial function; Lipoprotein; Nitric oxide; Reactive oxygen species