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

被引:487
作者
Besler, Christian [1 ,2 ,3 ]
Heinrich, Kathrin [1 ,2 ,3 ]
Rohrer, Lucia [3 ,4 ]
Doerries, Carola [1 ,2 ,3 ]
Riwanto, Meliana [1 ,2 ,3 ]
Shih, Diana M. [5 ]
Chroni, Angeliki [6 ]
Yonekawa, Keiko [1 ,2 ]
Stein, Sokrates [1 ,2 ,3 ]
Schaefer, Nicola [1 ,2 ,3 ]
Mueller, Maja [1 ,2 ]
Akhmedov, Alexander [1 ,2 ,3 ]
Daniil, Georgios [6 ]
Manes, Costantina [1 ,2 ]
Templin, Christian [1 ,2 ]
Wyss, Christophe [1 ,2 ]
Maier, Willibald [1 ,2 ]
Tanner, Felix C. [1 ,2 ,3 ]
Matter, Christian M. [1 ,2 ,3 ]
Corti, Roberto [1 ,2 ]
Furlong, Clement [7 ,8 ]
Lusis, Aldons J. [5 ]
von Eckardstein, Arnold [3 ,4 ]
Fogelman, Alan M. [5 ]
Luescher, Thomas F. [1 ,2 ,3 ]
Landmesser, Ulf [1 ,2 ,3 ]
机构
[1] Univ Zurich Hosp, Ctr Cardiovasc, CH-8091 Zurich, Switzerland
[2] Univ Zurich, Inst Physiol, Zurich, Switzerland
[3] Univ Zurich, Ctr Integrat Human Physiol, Zurich, Switzerland
[4] Univ Zurich Hosp, Inst Clin Chem, CH-8091 Zurich, Switzerland
[5] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA
[6] Natl Ctr Sci Res Demokritos, Inst Biol, Athens, Greece
[7] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA
[8] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA
基金
新加坡国家研究基金会; 瑞士国家科学基金会;
关键词
HIGH-DENSITY-LIPOPROTEIN; NITRIC-OXIDE SYNTHASE; SCAVENGER RECEPTOR-BI; ENDOTHELIAL PROGENITOR CELLS; APOLIPOPROTEIN-A-I; CHOLESTEROL EFFLUX; SERUM PARAOXONASE; EXPRESSION; BINDING; REENDOTHELIALIZATION;
D O I
10.1172/JCI42946
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 PKC beta II 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 PKC beta II-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 PKC beta II-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.
引用
收藏
页码:2693 / 2708
页数:16
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