Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease
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
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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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 8

Activity and content of HDL-associated PON1 in healthy subjects and patients with sCAD or ACS — effect of inhibition of PON1 on HDL-associated MDA content and phosphorylation of PKCβII at Ser660.

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Activity and content of HDL-associated PON1 in healthy subjects and pati...
(A) Paraoxonase and (B) arylesterase activities of HDL-associated PON1 isolated from healthy subjects and patients with sCAD or ACS, as measured by UV spectrophotometry (n = 25 per group). (C) PON1 content in HDL isolated from healthy subjects and patients with sCAD or ACS was determined by Western blot analysis (n = 25 per group). (D) Effect of the specific PON1 inhibitor hydroxyquinoline (HQ, 200 μM) on protein-bound MDA content and (E) MDA-lysine adducts in HDL, as detected by spectrophotometry and mass-spectrometry analysis, respectively (n = 4–6 per group). (F) Effect of HDL pretreated with the PON1 inhibitors HQ or EDTA (5 mM) on phosphorylation of PKCβII at Ser660 was detected by Western blot analysis (n = 8–10 per group).