Apolipoprotein E enhances endothelial-NO production by modulating caveolin 1 interaction with endothelial NO synthase.
Apolipoprotein E (apoE) is widely expressed in mammalian tissues, and one of the important tissue-specific effects is the atheroprotection ascribed to macrophage-derived apoE in the arterial wall. However, underlying mechanisms are not well understood. In this study, using subcellular fractionation, confocal microscopy, and coimmunoprecipitation, we demonstrated that macrophage-derived apoE is internalized by endothelial cells and impacts the subcellular distribution/interaction of caveolin 1 (cav-1) and endothelial NO synthase (eNOS). The addition of apoE disrupts the heteromeric complex formed between cav-1 and eNOS, and increases NO production. Sterol and oxysterol enhance endothelial cav-1/eNOS interaction and suppress NO production, but these effects are reversed by apoE. Silencing endothelial cav-1 attenuates apoE-induced NO production, establishing the importance of the cav-1-eNOS interaction for the increment in endothelial NO produced by apoE. Consistent with these observations, macrophage-derived apoE significantly improves vasodilation to acetylcholine in resistance arteries isolated from adipose tissue of obese humans. We conclude that macrophage-derived apoE enhances endothelial NO production by disrupting the inhibitory interaction of eNOS with cav-1. These results establish a novel mechanism by which apoE modulates endothelial cell function.
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Lili
L
Yue
Jing-Tan
JT
Bian
Ivana
I
Grizelj
Ana
A
Cavka
Shane A
SA
Phillips
Ayako
A
Makino
Theodore
T
Mazzone
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D050152:Intra-Abdominal Fat / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*
D001057:Apolipoproteins E; D051242:Caveolin 1; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III