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J. Biol. Chem., Vol. 276, Issue 17, 14212-14221, April 27, 2001
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From the Center of Vascular Biology and Medicine,
Friedrich-Schiller-University of Jena, 99089 Erfurt, Germany and the
Hypochlorous acid/hypochlorite,
generated by the
myeloperoxidase/H2O2/halide system of
activated phagocytes, has been shown to oxidize/modify low density
lipoprotein (LDL) in vitro and may be involved in the
formation of atherogenic lipoproteins in vivo. Accordingly,
hypochlorite-modified (lipo)proteins have been detected in human
atherosclerotic lesions where they colocalize with macrophages and
endothelial cells. The present study investigates the influence of
hypochlorite-modified LDL on endothelial synthesis of nitric oxide (NO)
measured as formation of citrulline (coproduct of NO) and cGMP (product
of the NO-activated soluble guanylate cyclase) upon cell stimulation
with thrombin or ionomycin. Pretreatment of human umbilical vein
endothelial cells with hypochlorite-modified LDL led to a time- and
concentration-dependent inhibition of agonist-induced citrulline and cGMP synthesis compared with preincubation of cells with
native LDL. This inhibition was neither due to a decreased expression
of endothelial NO synthase (eNOS) nor to a deficiency of its cofactor
tetrahydrobiopterin. Likewise, the uptake of L-arginine, the substrate of eNOS, into the cells was not affected.
Hypochlorite-modified LDL caused remarkable changes of intracellular
eNOS distribution including translocation from the plasma membrane and
disintegration of the Golgi location without altering myristoylation or
palmitoylation of the enzyme. In contrast, cyclodextrin known to
deplete plasma membrane of cholesterol and to disrupt caveolae induced
only a disappearance of eNOS from the plasma membrane that was not
associated with decreased agonist-induced citrulline and cGMP
formation. The present findings suggest that mislocalization of NOS
accounts for the reduced NO formation in human umbilical vein
endothelial cells treated with hypochlorite-modified LDL and point to
an important role of Golgi-located NOS in these processes. We conclude
that inhibition of NO synthesis by hypochlorite-modified LDL may be an
important mechanism in the development of endothelial dysfunction and
early pathogenesis of atherosclerosis.
Hypochlorite-modified Low Density Lipoprotein Inhibits Nitric
Oxide Synthesis in Endothelial Cells via an Intracellular
Dislocalization of Endothelial Nitric-oxide Synthase*
,, and Institute of Medical Biochemistry and Molecular Biology,
Karl-Franzens-University, A-8010 Graz, Austria
*
This work was supported by Deutsche Forschungsgemeinschaft
Grant HE 2304/1-1 (to R. H.) and the Fonds zur Foerderung der
Wissenschaftlichen Forschung Grant P14186 (to E. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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