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.
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
Usage data is cumulative from April 2024 through April 2025.
Usage | JCI | PMC |
---|---|---|
Text version | 1,322 | 88 |
106 | 51 | |
Figure | 421 | 4 |
Table | 46 | 0 |
Supplemental data | 45 | 2 |
Citation downloads | 85 | 0 |
Totals | 2,025 | 145 |
Total Views | 2,170 |
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.