Carbamylated low-density lipoprotein induces endothelial dysfunction.
- Speer T 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.
- Owala FO University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
- Holy EW University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
- Zewinger S Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
- Frenzel FL Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
- Stähli BE University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
- Razavi M Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
- Triem S Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
- Cvija H Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
- Rohrer L Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
- Seiler S Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
- Heine GH Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
- Jankowski V Department of Internal Medicine IV, Charité-Universitätsmedizin, Berlin, Germany.
- Jankowski J Department of Internal Medicine IV, Charité-Universitätsmedizin, Berlin, Germany.
- Camici GG Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
- Akhmedov A Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
- Fliser D Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany.
- Lüscher TF University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.
- Tanner FC 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.
- 2014-03-25
Published in:
- European heart journal. - 2014
Carbamylation
Endothelial function
Lipoprotein
Nitric oxide
Reactive oxygen species
Acetylcholine
Analysis of Variance
Animals
Aorta
Cardiovascular Diseases
Endothelium, Vascular
Enzyme Inhibitors
Healthy Volunteers
Humans
In Vitro Techniques
Lipoproteins, LDL
Mice, Inbred C57BL
Mice, Transgenic
Nitric Oxide Synthase Type III
Onium Compounds
Reactive Oxygen Species
Renal Insufficiency, Chronic
Scavenger Receptors, Class E
Vasodilation
Vasodilator Agents
English
AIMS
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.
METHODS AND 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.
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.
METHODS AND 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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1093/eurheartj/ehu111
- PMID 24658767
- Persistent URL
- https://sonar.rero.ch/global/documents/12740
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