Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease
Christian Besler, … , Thomas F. Lüscher, Ulf Landmesser
Christian Besler, … , Thomas F. Lüscher, Ulf Landmesser
Published June 23, 2011
Citation Information: J Clin Invest. 2011;121(7):2693-2708. https://doi.org/10.1172/JCI42946.
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Research Article

Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease

Abstract

Therapies that raise levels of HDL, which is thought to exert atheroprotective effects via effects on endothelium, are being examined for the treatment or prevention of coronary artery disease (CAD). However, the endothelial effects of HDL are highly heterogeneous, and the impact of HDL of patients with CAD on the activation of endothelial eNOS and eNOS-dependent pathways is unknown. Here we have demonstrated that, in contrast to HDL from healthy subjects, HDL from patients with stable CAD or an acute coronary syndrome (HDLCAD) does not have endothelial antiinflammatory effects and does not stimulate endothelial repair because it fails to induce endothelial NO production. Mechanistically, this was because HDLCAD activated endothelial lectin-like oxidized LDL receptor 1 (LOX-1), triggering endothelial PKCβII activation, which in turn inhibited eNOS-activating pathways and eNOS-dependent NO production. We then identified reduced HDL-associated paraoxonase 1 (PON1) activity as one molecular mechanism leading to the generation of HDL with endothelial PKCβII-activating properties, at least in part due to increased formation of malondialdehyde in HDL. Taken together, our data indicate that in patients with CAD, HDL gains endothelial LOX-1– and thereby PKCβII-activating properties due to reduced HDL-associated PON1 activity, and that this leads to inhibition of eNOS-activation and the subsequent loss of the endothelial antiinflammatory and endothelial repair–stimulating effects of HDL.

Authors

Christian Besler, Kathrin Heinrich, Lucia Rohrer, Carola Doerries, Meliana Riwanto, Diana M. Shih, Angeliki Chroni, Keiko Yonekawa, Sokrates Stein, Nicola Schaefer, Maja Mueller, Alexander Akhmedov, Georgios Daniil, Costantina Manes, Christian Templin, Christophe Wyss, Willibald Maier, Felix C. Tanner, Christian M. Matter, Roberto Corti, Clement Furlong, Aldons J. Lusis, Arnold von Eckardstein, Alan M. Fogelman, Thomas F. Lüscher, Ulf Landmesser

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Figure 7

Critical role of HDL-associated MDA in the impaired capacity of HDL to increase endothelial NO production and in the increased stimulation of PKCβII by HDL.

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Critical role of HDL-associated MDA in the impaired capacity of HDL to i...
(A) Protein-bound MDA content in HDL from healthy subjects and patients with sCAD or ACS was measured by spectrophotometry, as described in more detail in Methods (n = 12–14 per group). (B) Mass spectrometry analysis of MDA-lysine adducts in HDL from healthy subjects and patients with CAD (n = 4 per group). (C) Effect of MDA-modified HDL on endothelial NO production, as measured by ESR spectroscopy (n = 8 per group). (D) Inhibition of endothelial LOX-1 with a specific blocking antibody partially prevented the decrease in endothelial NO production in response to MDA-modified HDL (12.5 mol MDA/mol apoA-I; n = 6 per group). (E) Modification of HDL by MDA (12.5 mol MDA/mol apoA-I; n = 6 per group) resulted in an increased activation of endothelial PKCβII that was prevented by a specific blocking antibody against endothelial LOX-1 (n = 6–10 per group).