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(Circulation. 2003;107:2607.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Critical Role of L-Arginine in Endothelial Cell Survival During Oxidative Stress

Christoph V. Suschek, PhD; Oliver Schnorr, PhD; Karsten Hemmrich; Olivier Aust, PhD; Lars-Oliver Klotz, PhD; Helmut Sies, MD; Victoria Kolb-Bachofen, PhD

From the Research Group Immunobiology (C.V.S., O.S., K.H., V.K.-B.) and Institute of Biochemistry and Molecular Medicine I and Biologisch-Medizinisches Forschungszentrum (O.A., L.-O.K., H.S.), Heinrich-Heine-University Duesseldorf, Germany.

Correspondence to Dr Christoph V. Suschek, Research Group Immunobiology, Geb.: 23.12.02, Heinrich-Heine-University Duesseldorf, PO Box 10 10 07, D-40001 Duesseldorf, Germany. E-mail suschek{at}uni-duesseldorf.de

Background— Oxidative damage of vascular endothelium represents an important initiation step in the development of atherosclerosis. Recently, we reported about protection of inducible nitric oxide synthase (iNOS)-derived high-output NO in endothelial cells. Because iNOS activity critically depends on the availability of its substrate L-arginine, the present study aims at elucidating iNOS-mediated effects on H₂O₂-induced apoptosis of cytokine-activated rat aortic endothelial cells (AECs) subject to medium L-arginine concentrations.

Methods and Results— In cytokine-activated AECs, iNOS activity was found to be half-maximal at 60 µmol/L arginine, which represents the medium serum level in rats but also in humans. Maximal activity is seen at and above 200 µmol/L arginine. Activated cells grown in the absence of arginine with minimal iNOS activity are highly sensitive toward H₂O₂-induced apoptosis, and increases in medium arginine concentrations result in increased cell survival. Moreover, competition experiments show that iNOS activity is completely dependent on cationic amino acid transporter-mediated arginine uptake. We also find that the arginine-dependent protection includes inhibition of endothelial lipid peroxidation and increases in the expression of vasoprotective stress response genes.

Conclusions— Our data demonstrate that arginine concentrations corresponding to physiological serum levels do not allow for optimal endothelial iNOS activity. Thus, decreases in systemic arginine concentrations, or locally within atherosclerotic plaques, will impair the endothelial iNOS-mediated stress response and will significantly increase the risk of endothelial dysfunction.

Key Words: amino acids • arteriosclerosis • endothelium • inflammation • nitric oxide

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