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(Circulation. 2000;101:1261.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Effect of Native and Oxidized Low-Density Lipoprotein on Endothelial Nitric Oxide and Superoxide Production
Key Role of L-Arginine Availability
From the Second Department of Internal Medicine, University of Ferrara (Italy) (L.V., F.R., A.P., N.M., G.Z., R.F.), and the Center for Biomedical Research, Oakland University, Rochester, Mich (S.H., V.B., T.M.).
Correspondence to Tadeusz Malinski, PhD, Center for Biomedical Research, Oakland University, Rochester, MI 48309-4477. E-mail flr{at}ifeuniv.unife.it
Background—Native and oxidized LDLs (n-LDL and ox-LDL) are involved in the atherogenic process and affect endothelium-dependent vascular tone through their interaction with nitric oxide (NO).
Methods and Results—In this study we evaluated directly, by using a porphyrinic microsensor, the effect of increasing lipoprotein concentrations on endothelial NO and superoxide (O2-) production. We investigated where lipoproteins may affect the L-arginine–NO pathway by pretreating cells with L-arginine, L-N-arginine methyl ester (L-NAME), and superoxide dismutase. Bovine aortic endothelial cells were exposed for 1 hour to increasing concentrations of n-LDL (from 0 to 240 mg cholesterol/dL) and ox-LDL (from 0 to 140 mg cholesterol/dL). A stimulated (calcium ionophore) NO concentration decreased to 29% of the control at n-LDL concentration of 80 mg cholesterol/dL and to 15% of the control at 20 mg cholesterol/dL of ox-LDL. L-Arginine partially neutralized the inhibitory effect of n-LDL and ox-LDL on the NO generation. Superoxide dismutase pretreatment did not modify NO production, whereas L-NAME blunted NO generation at all LDL concentrations. O2- production was increased at low n-LDL and very low ox-LDL concentrations; this was reversed by L-arginine.
Conclusions—These findings confirm the inhibitory role of n-LDL and ox-LDL on NO generation and suggest that lipoproteins may induce a decreased uptake of L-arginine. The local depletion of the L-arginine substrate may derange the NO synthase, leading to overproduction of O2- from oxygen, the other substrate of NO synthase.
Key Words: nitric oxide • endothelium • lipoproteins
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