L-4F, an apolipoprotein A-1 mimetic, restores nitric oxide and superoxide anion balance in low-density lipoprotein-treated endothelial cells.

Abstract:

BACKGROUND:Low-density lipoprotein (LDL) impairs endothelial cell function by uncoupling endothelial nitric oxide synthase (eNOS) activity, which allows superoxide anion (O2*-)) to be generated rather than nitric oxide (*NO). Recent reports indicate that apolipoprotein (apo) A-1 mimetics inhibit the development of atherosclerotic lesions in LDL receptor-null mice. Here we hypothesize that L-4F, an apoA-1 mimetic that inhibits atherosclerosis induced by hypercholesterolemia, protects endothelial cell function by preventing LDL from uncoupling eNOS activity. METHODS AND RESULTS:Bovine aortic endothelial cells were incubated with LDL+/-L-4F, and changes in A23187-stimulated.NO and O2*- generation were determined by ozone chemiluminescence and superoxide dismutase-inhibitable ferricytochrome c reduction, respectively. Western analysis of eNOS immunoprecipitates was used to determine effects of LDL and L-4F on heat shock protein 90 (hsp90) interactions with eNOS. LDL decreased.NO production and increased eNOS-dependent O2*- generation. Pretreatment of LDL with L-4F increased.NO and decreased O2*- generation. By itself, L-4F had no effect on O2*- but did increase *NO generation. Stimulation of endothelial cells incubated with LDL decreased the association of hsp90 with eNOS. Pretreatment of LDL with L-4F prevented a decrease in hsp90 association with eNOS and often enhanced association on stimulation. CONCLUSIONS:These data demonstrate that L-4F protects endothelial cell function by preventing LDL from uncoupling eNOS activity. L-4F allows endothelial cell to maintain coupled eNOS activity to generate.NO even in the face of atherogenic concentrations of LDL.

journal_name

Circulation

journal_title

Circulation

authors

Ou Z,Ou J,Ackerman AW,Oldham KT,Pritchard KA Jr

doi

10.1161/01.cir.0000061949.17174.b6

subject

Has Abstract

pub_date

2003-03-25 00:00:00

pages

1520-4

issue

11

eissn

0009-7322

issn

1524-4539

journal_volume

107

pub_type

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