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L-4F, an apolipoprotein A-1 mimetic, restores nitric oxide and superoxide anion balance in low-density lipoprotein-treated endothelial cells. Circulation 2003 Mar 25;107(11):1520-4

Date

03/26/2003

Pubmed ID

12654610

DOI

10.1161/01.cir.0000061949.17174.b6

Scopus ID

2-s2.0-0037465731   85 Citations

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.

Author List

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

Authors

Keith T. Oldham MD Professor in the Surgery department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Apolipoprotein A-I
Cattle
Cells, Cultured
Endothelium, Vascular
HSP90 Heat-Shock Proteins
Lipoproteins, LDL
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type III
Peptides
Superoxides
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a