title: 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.affiliation: Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Besler
authors.forename: Kathrin
authors.initials: K
authors.lastname: Heinrich
authors.forename: Lucia
authors.initials: L
authors.lastname: Rohrer
authors.forename: Carola
authors.initials: C
authors.lastname: Doerries
authors.forename: Meliana
authors.initials: M
authors.lastname: Riwanto
authors.forename: Diana M
authors.initials: DM
authors.lastname: Shih
authors.forename: Angeliki
authors.initials: A
authors.lastname: Chroni
authors.forename: Keiko
authors.initials: K
authors.lastname: Yonekawa
authors.forename: Sokrates
authors.initials: S
authors.lastname: Stein
authors.forename: Nicola
authors.initials: N
authors.lastname: Schaefer
authors.forename: Maja
authors.initials: M
authors.lastname: Mueller
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.forename: Georgios
authors.initials: G
authors.lastname: Daniil
authors.forename: Costantina
authors.initials: C
authors.lastname: Manes
authors.forename: Christian
authors.initials: C
authors.lastname: Templin
authors.forename: Christophe
authors.initials: C
authors.lastname: Wyss
authors.forename: Willibald
authors.initials: W
authors.lastname: Maier
authors.forename: Felix C
authors.initials: FC
authors.lastname: Tanner
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
authors.forename: Roberto
authors.initials: R
authors.lastname: Corti
authors.forename: Clement
authors.initials: C
authors.lastname: Furlong
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D043303:Aryldialkylphosphatase / Q000378:metabolism; D003324:Coronary Artery Disease / Q000378:metabolism / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D008075:Lipoproteins, HDL; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human