Carbamylated low-density lipoprotein induces endothelial dysfunction
Thimoteus Speer1, Frederick O Owala2, Erik W Holy2
1University 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.
Insights
Carbamylation of low-density lipoproteins (LDL) impairs endothelial function and increases cardiovascular risk in chronic kidney disease (CKD) patients. This study reveals a novel mechanism in atherosclerosis pathogenesis.
Area of Science:
- Cardiovascular Research
- Atherosclerosis Pathogenesis
- Endothelial Dysfunction
Background:
- Cardiovascular events are a leading cause of death, with atherosclerosis driven by low-density lipoproteins (LDL).
- Carbamylation of LDL, particularly in chronic kidney disease (CKD), may alter lipoprotein function.
- The impact of carbamylated LDL on endothelial function is not well understood.
Purpose of the Study:
- To investigate the effect of carbamylated LDL (cLDL) on endothelial function.
- To elucidate the mechanisms underlying cLDL-induced endothelial dysfunction.
- To assess the prognostic value of LDL carbamylation in CKD patients.
Main Methods:
- Isolated and carbamylated native LDL (nLDL).
- Assessed vascular reactivity in mouse aortic rings and measured reactive oxygen species (ROS) and nitric oxide (NO) production.
- Correlated LDL carbamylation levels with cardiovascular outcomes in CKD patients.
Main Results:
- Carbamylated LDL impaired endothelium-dependent relaxation and increased ROS production.
- cLDL activated NADPH-oxidase and promoted eNOS uncoupling via S-glutathionylation.
- LOX-1 receptor exacerbated cLDL-induced endothelial dysfunction.
- Higher LDL carbamylation levels predicted cardiovascular events and mortality in CKD patients.
Conclusions:
- LDL carbamylation induces endothelial dysfunction through LOX-1 activation and ROS generation, leading to eNOS uncoupling.
- This represents a novel mechanism in atherosclerosis development.
- LDL carbamylation is pathogenic and prognostic in CKD patients with elevated cLDL levels.
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.
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