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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-48656

Besler, C; Heinrich, K; Rohrer, L; Doerries, C; Riwanto, M; Shih, D M; Chroni, A; Yonekawa, K; Stein, S; Schaefer, N; Mueller, M; Akhmedov, A; Daniil, G; Manes, C; Templin, C; Wyss, C; Maier, W; Tanner, F C; Matter, C M; Corti, R; Furlong, C; Lusis, A J; von Eckardstein, Arnold; Fogelman, A M; Lüscher, T F; Landmesser, U (2011). Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. Journal of Clinical Investigation, 121(7):2693-708.

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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.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
DDC:570 Life sciences; biology
610 Medicine & health
540 Chemistry
Language:English
Date:2011
Deposited On:14 Jul 2011 08:45
Last Modified:16 Jul 2014 22:24
Publisher:American Society for Clinical Investigation
ISSN:0021-9738
Publisher DOI:10.1172/JCI42946
PubMed ID:21701070
Citations:Web of Science®. Times Cited: 115
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Scopus®. Citation Count: 127

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