© 1995 American Heart Association, Inc.
Articles |
Native Low-Density Lipoprotein Increases Endothelial Cell Nitric Oxide Synthase Generation of Superoxide Anion
Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993, and in full at the International Symposium on Endothelium-Derived Factors and Vascular Protection, San Francisco, Calif, January 21-25, 1995.
From the Department of Pathology (K.A.P, D.M.S.), CardioVascular Research Center, Medical College of Wisconsin, Milwaukee; the Departments of Experimental Pathology (L.G., M.W., P.V., M.B.S.) and Physiology (M.S.W.), New York Medical College, Valhalla; and Boyer Center for Molecular Medicine (W.C.S.), Yale University School of Medicine, New Haven, Conn.
Correspondence to Kirkwood A. Pritchard, Jr, PhD, Associate Professor of Pathology and Pharmacology and Toxicology, Medical College of Wisconsin, CardioVascular Research Center, Rm 494B, 8701 W Watertown Plank Rd, Milwaukee, WI 53226.
Abstract To examine mechanisms by which native low-density
lipoprotein (n-LDL) perturbs endothelial cell (EC)
release of superoxide anion (O2-) and nitric
oxide (NO), ECs were incubated with n-LDL at 240 mg
cholesterol per deciliter for 4 days with media changes
every 24 hours. n-LDL increases EC release of
O2- by more than fourfold and increases
nitrite production by 57%. In the conditioned media from day-4
incubations, n-LDL increases total nitrogen oxides 20 times control EC
(C-EC) levels. However, n-LDL did not alter EC NO synthase (eNOS)
enzyme activity as measured by the [3H]citrulline assay.
N
-Nitro-L-arginine methyl
ester, a specific inhibitor of eNOS activity, increases
C-EC release of O2- by >300% but decreases
LDL-treated EC (LDL-EC) release by >95%. L-Arginine
inhibits the release of O2- from LDL-ECs by
>95% but did not effect C-EC release of O2-.
Indomethacin and SKF 525A partially attenuate
LDL-induced increases in O2-
production by 
50% and 30%, respectively. Thus,
n-LDL increases O2- and NO production,
which increases the likelihood of the formation of peroxynitrite
(ONOO-), a potent oxidant. n-LDL increases the levels of
nitrotyrosine, a stable oxidation product of
ONOO-, and tyrosine by 50%. In spite of this
increase in oxidative metabolism, analysis of
thiobarbituric acid substances reveals that no significant changes in
the oxidation of n-LDL occur during the 24-hour incubations with ECs.
These data indicate that n-LDL directly perturbs
endothelial oxidative metabolism and
uncouples L-arginine metabolism from NO
release to increase eNOS generation of O2-.
Such changes may represent one of the earliest EC perturbations
in atherogenesis.
Key Words: low-density lipoprotein • reactive oxygen species • atherogenesis • peroxynitrite • superoxide anion peroxynitrite
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