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.
View: Text | PDF
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

×

Figure 10

Effects of HDL isolated from Pon1-deficient mice or their wild-type littermates on endothelial cell NO production, superoxide production, and endothelial inflammatory activation.

Options: View larger image (or click on image) Download as PowerPoint
Effects of HDL isolated from Pon1-deficient mice or their wild-type litt...
(A) In contrast to HDL from wild-type littermates, HDL isolated from Pon1-deficient mice inhibited rather than stimulated NO production in mouse aortic endothelial cells, as detected by ESR spectroscopy analysis (n = 5 per group). (B) In addition, HDL from Pon1-deficient mice failed to inhibit basal and TNF-α–stimulated superoxide production in mouse aortic endothelial cells (ESR spectroscopy analysis, n = 5–7 per group). (C) Whereas HDL from wild-type littermates potently inhibited endothelial inflammatory activation, HDL from Pon1-deficient mice did not inhibit TNF-α–stimulated VCAM-1 expression and (D) endothelial monocyte adhesion (n = 5–6 per group). (E) Supplementation of HDL from Pon1-deficient mice with purified PON1 (5 U/100 μg HDL protein) partially restored the capacity of HDL to stimulate endothelial NO production as measured by ESR spectroscopy (n = 5–6 per group).