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Carbamylated low-density lipoprotein induces endothelial dysfunction

Speer, Thimoteus ; Owala, Frederick O. ; Holy, Erik W. ; Zewinger, Stephen ; Frenzel, Felix L. ; Stähli, Barbara E. ; Razavi, Marjan ; Triem, Sarah ; Cvija, Hrvoje ; Rohrer, Lucia ; Seiler, Sarah ; Heine, Gunnar H. ; Jankowski, Vera ; Jankowski, Joachim ; Camici, Giovanni G. ; Akhmedov, Alexander ; Fliser, Danilo ; Lüscher, Thomas F. ; Tanner, Felix C.

In: European Heart Journal, 2014, vol. 35, no. 43, p. 3021-3032

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    Title
    • Carbamylated low-density lipoprotein induces endothelial dysfunction
    Author
    • Speer, Thimoteus. University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland
    • Owala, Frederick O.. University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland
    • Holy, Erik W.. University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland
    • Zewinger, Stephen. Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany
    • Frenzel, Felix L.. Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany
    • Stähli, Barbara E.. University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland
    • Razavi, Marjan. Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
    • Triem, Sarah. Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany
    • Cvija, Hrvoje. Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany
    • Rohrer, Lucia. Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland
    • Seiler, Sarah. Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany
    • Heine, Gunnar H.. Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany
    • Jankowski, Vera. Department of Internal Medicine IV, Charité-Universitätsmedizin, Berlin, Germany
    • Jankowski, Joachim. Department of Internal Medicine IV, Charité-Universitätsmedizin, Berlin, Germany
    • Camici, Giovanni G.. Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
    • Akhmedov, Alexander. Center of Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland
    • Fliser, Danilo. Department of Internal Medicine 4, Saarland University Hospital, Homburg/Saar, Germany
    • Lüscher, Thomas F.. University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland
    • Tanner, Felix C.. University Heart Center, Cardiovascular Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland
    Document Type
    • Postprint
    OAI-PMH Identifier
    • oai:doc.rero.ch:290608
    Summary
    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