Thimoteus Speer1, Frederick O Owala2, Erik W Holy2, Stephen Zewinger3, Felix L Frenzel3, Barbara E Stähli2, Marjan Razavi4, Sarah Triem3, Hrvoje Cvija3, Lucia Rohrer5, Sarah Seiler3, Gunnar H Heine3, Vera Jankowski6, Joachim Jankowski6, Giovanni G Camici4, Alexander Akhmedov4, Danilo Fliser3, Thomas F Lüscher2, Felix C Tanner7. 1. 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. 2. University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland. 3. Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany. 4. Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland. 5. Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland. 6. Department of Internal Medicine IV, Charité-Universitätsmedizin, Berlin, Germany. 7. 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.
Abstract
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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-1transgenic 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Zeneng Wang; Joseph A DiDonato; Jennifer Buffa; Suzy A Comhair; Mark A Aronica; Raed A Dweik; Nancy A Lee; James J Lee; Mary Jane Thomassen; Mani Kavuru; Serpil C Erzurum; Stanley L Hazen Journal: J Biol Chem Date: 2016-09-01 Impact factor: 5.157