© 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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P. A. Kaufmann, T. Gnecchi-Ruscone, K. P. Schafers, T. F. Luscher, and P. G. Camici Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia J. Am. Coll. Cardiol., July 1, 2000; 36(1): 103 - 109. [Abstract] [Full Text] [PDF]
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E. S. G. Stroes, E. E. van Faassen, M. Yo, P. Martasek, P. Boer, R. Govers, and T. J. Rabelink Folic Acid Reverts Dysfunction of Endothelial Nitric Oxide Synthase Circ. Res., June 9, 2000; 86(11): 1129 - 1134. [Abstract] [Full Text] [PDF]
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M. S. Wolin Interactions of Oxidants With Vascular Signaling Systems Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1430 - 1442. [Abstract] [Full Text] [PDF]
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U. Landmesser, R. Merten, S. Spiekermann, K. Buttner, H. Drexler, and B. Hornig Vascular Extracellular Superoxide Dismutase Activity in Patients With Coronary Artery Disease : Relation to Endothelium-Dependent Vasodilation Circulation, May 16, 2000; 101(19): 2264 - 2270. [Abstract] [Full Text] [PDF]
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T. J. Guzik, N. E. J. West, E. Black, D. McDonald, C. Ratnatunga, R. Pillai, and K. M. Channon Vascular Superoxide Production by NAD(P)H Oxidase : Association With Endothelial Dysfunction and Clinical Risk Factors Circ. Res., May 12, 2000; 86 (9): e85 - e90. [Abstract] [Full Text] [PDF]
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K. Kauser, V. da Cunha, R. Fitch, C. Mallari, and G. M. Rubanyi Role of endogenous nitric oxide in progression of atherosclerosis in apolipoprotein E-deficient mice Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1679 - H1685. [Abstract] [Full Text] [PDF]
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L. Vergnani, S. Hatrik, F. Ricci, A. Passaro, N. Manzoli, G. Zuliani, V. Brovkovych, R. Fellin, and T. Malinski Effect of Native and Oxidized Low-Density Lipoprotein on Endothelial Nitric Oxide and Superoxide Production : Key Role of L-Arginine Availability Circulation, March 21, 2000; 101(11): 1261 - 1266. [Abstract] [Full Text] [PDF]
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L. P. Perrault, F. Mahlberg, C. Breugnot, J.-P. Bidouard, N. Villeneuve, J.-P. Vilaine, and P. M. Vanhoutte Hypercholesterolemia Increases Coronary Endothelial Dysfunction, Lipid Content, and Accelerated Atherosclerosis After Heart Transplantation Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20(3): 728 - 736. [Abstract] [Full Text] [PDF]
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R. Golser, A. C. F. Gorren, A. Leber, P. Andrew, H.-J. Habisch, E. R. Werner, K. Schmidt, R. C. Venema, and B. Mayer Interaction of Endothelial and Neuronal Nitric-oxide Synthases with the Bradykinin B2 Receptor. BINDING OF AN INHIBITORY PEPTIDE TO THE OXYGENASE DOMAIN BLOCKS UNCOUPLED NADPH OXIDATION J. Biol. Chem., February 25, 2000; 275(8): 5291 - 5296. [Abstract] [Full Text] [PDF]
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T. Munzel, H. Li, H. Mollnau, U. Hink, E. Matheis, M. Hartmann, M. Oelze, M. Skatchkov, A. Warnholtz, L. Duncker, et al. Effects of Long-Term Nitroglycerin Treatment on Endothelial Nitric Oxide Synthase (NOS III) Gene Expression, NOS III-Mediated Superoxide Production, and Vascular NO Bioavailability Circ. Res., January 7, 2000; 86 (1): e7 - e12. [Abstract] [Full Text] [PDF]
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A. A. Ogonowski, W. H. Kaesemeyer, L. Jin, V. Ganapathy, F. H. Leibach, and R. W. Caldwell Effects of NO donors and synthase agonists on endothelial cell uptake of L-Arg and superoxide production Am J Physiol Cell Physiol, January 1, 2000; 278(1): C136 - C143. [Abstract] [Full Text] [PDF]
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C. Palombo, V. Lubrano, and T. Sampietro Oxidative stress, F2-isoprostanes and endothelial dysfunction in hypercholesterolemia Cardiovasc Res, December 1, 1999; 44(3): 474 - 476. [Full Text] [PDF]
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D. D. Gutterman Adventitia-dependent influences on vascular function Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1265 - H1272. [Full Text] [PDF]
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M. McIntyre, D. F. Bohr, and A. F. Dominiczak Endothelial Function in Hypertension : The Role of Superoxide Anion Hypertension, October 1, 1999; 34(4): 539 - 545. [Abstract] [Full Text] [PDF]
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P. J Andrew and B. Mayer Enzymatic function of nitric oxide synthases Cardiovasc Res, August 15, 1999; 43(3): 521 - 531. [Abstract] [Full Text] [PDF]
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I. Fleming and R. Busse Signal transduction of eNOS activation Cardiovasc Res, August 15, 1999; 43(3): 532 - 541. [Abstract] [Full Text] [PDF]
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W. Linz, P. Wohlfart, B. A Scholkens, T. Malinski, and G. Wiemer Interactions among ACE, kinins and NO Cardiovasc Res, August 15, 1999; 43(3): 549 - 561. [Full Text] [PDF]
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H. Drexler Nitric oxide and coronary endothelial dysfunction in humans Cardiovasc Res, August 15, 1999; 43(3): 572 - 579. [Full Text] [PDF]
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G. Kojda and D. Harrison Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure Cardiovasc Res, August 15, 1999; 43(3): 652 - 671. [Full Text] [PDF]
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 A. J. Gow, F. Branco, M. Christofidou-Solomidou, L. Black-Schultz, S. M. Albelda, and V. R. Muzykantov Immunotargeting of glucose oxidase: intracellular production of H2O2 and endothelial oxidative stress Am J Physiol Lung Cell Mol Physiol, August 1, 1999; 277(2): L271 - L281. [Abstract] [Full Text] [PDF]
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F. Cosentino and T. F Luscher Tetrahydrobiopterin and endothelial nitric oxide synthase activity Cardiovasc Res, August 1, 1999; 43(2): 274 - 278. [Full Text] [PDF]
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J. R. Kersten and D. C. Warltier Modulation of the adaptive response to myocardial ischemia by coexisting disease Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H2268 - H2270. [Full Text] [PDF]
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K. Kusterer, T. Pohl, H.-P. Fortmeyer, W. Marz, H. Scharnagl, A. Oldenburg, S. Angermuller, I. Fleming, K. H. Usadel, and R. Busse Chronic selective hypertriglyceridemia impairs endothelium-dependent vasodilatation in rats Cardiovasc Res, June 1, 1999; 42(3): 783 - 793. [Abstract] [Full Text] [PDF]
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R. Wever, P. Boer, M. Hijmering, E. Stroes, M. Verhaar, J. Kastelein, K. Versluis, F. Lagerwerf, H. van Rijn, H. Koomans, et al. Nitric Oxide Production Is Reduced in Patients With Chronic Renal Failure Arterioscler. Thromb. Vasc. Biol., May 1, 1999; 19(5): 1168 - 1172. [Abstract] [Full Text] [PDF]
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S. A. Gupte, T. Rupawalla, K. M. Mohazzab-H., and M. S. Wolin Regulation of NO-elicited pulmonary artery relaxation and guanylate cyclase activation by NADH oxidase and SOD Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1535 - H1542. [Abstract] [Full Text] [PDF]
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S. R. Thom, D. Fisher, Y. A. Xu, S. Garner, and H. Ischiropoulos Role of nitric oxide-derived oxidants in vascular injury from carbon monoxide in the rat Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H984 - H992. [Abstract] [Full Text] [PDF]
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T. Heitzer, S. Y. Herttuala, E. Wild, J. Luoma, and H. Drexler Effect of vitamin E on endothelial vasodilator function in patients with hypercholesterolemia, chronic smoking or both J. Am. Coll. Cardiol., February 1, 1999; 33(2): 499 - 505. [Abstract] [Full Text] [PDF]
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I. J. Kullo, R. D. Simari, and R. S. Schwartz Vascular Gene Transfer : From Bench to Bedside Arterioscler. Thromb. Vasc. Biol., February 1, 1999; 19(2): 196 - 207. [Full Text] [PDF]
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W. H. Kaesemeyer, R. B. Caldwell, J. Huang, and R. W. Caldwell Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions J. Am. Coll. Cardiol., January 1, 1999; 33(1): 234 - 241. [Abstract] [Full Text] [PDF]
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T. Marumo, V. B. Schini-Kerth, R. P. Brandes, and R. Busse Glucocorticoids Inhibit Superoxide Anion Production and p22 Phox mRNA Expression in Human Aortic Smooth Muscle Cells Hypertension, December 1, 1998; 32(6): 1083 - 1088. [Abstract] [Full Text] [PDF]
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Y. Xia, A.-L. Tsai, V. Berka, and J. L. Zweier Superoxide Generation from Endothelial Nitric-oxide Synthase. A Ca2+/CALMODULIN-DEPENDENT AND TETRAHYDROBIOPTERIN REGULATORY PROCESS J. Biol. Chem., October 2, 1998; 273(40): 25804 - 25808. [Abstract] [Full Text] [PDF]
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