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Originally published In Press as doi:10.1074/jbc.M210806200 on April 10, 2003
J. Biol. Chem., Vol. 278, Issue 25, 22901-22907, June 20, 2003
Expression of Inducible Nitric-oxide Synthase and Intracellular Protein Tyrosine Nitration in Vascular Smooth Muscle Cells
ROLE OF REACTIVE OXYGEN SPECIES*
Diana M. Fries   ¶,
Evgenia Paxinou ,
Marios Themistocleous ,
Eric Swanberg ,
Kathy K. Griendling ||,
Daniela Salvemini **,
Jan W. Slot  ,
Harry F. G. Heijnen ,
Stanley L. Hazen ¶¶ and
Harry Ischiropoulos ||||
From the
Stokes Research Institute, Children's Hospital of Pennsylvania and University of Pennsylvania, Philadelphia, Pennsylvania 19140, ||Department of Medicine, Division of Cardiology, Emory University, Atlanta, Georgia 30322, **MetaPhore Pharmaceuticals, Inc., St. Louis, Missouri 63114, Department of Cell Biology, University of Utrecht, Utrecht, Netherlands, Department of Hematology, University Medical Center, Utrecht, Netherlands, ¶¶Departments of Cell Biology and Cardiovascular Medicine, Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, Cleveland, Ohio 44195, and ¶Ministry of Health, Sao Paulo, SP, Brazil
A significant increase in the induction of inducible nitric-oxide synthase (iNOS) protein expression and in the levels of nitrite plus nitrate was observed in rat aortic smooth muscle cells (RASMCs) stably transfected with catalase (RASMC-2C2) as compared with empty vector-transfected RASMC-V4 cells after exposure to cytokines and lipopolysaccharide. The increased expression of iNOS protein in the RASMC-2C2 cells was associated with a significant activation of nuclear transcription factor  B, one of the transcriptional regulators of iNOS expression. The induction of iNOS was also accompanied by increased protein tyrosine nitration in both cell types as revealed by immunocytochemical staining and high pressure liquid chromatography with on-line electrospray ionization tandem mass spectrometry. Nitrotyrosine formation was inhibited by 1400W, an iNOS inhibitor, by 4-(2-aminoethyl) benzenesulfonyl fluoride, an inhibitor of NADPH oxidase, and by the superoxide dismutase mimetic M40403, but not by the peroxidase inhibitor 4-aminobenzoic hydrazide. Electron microscopy using affinity-purified anti-nitrotyrosine antibodies revealed labeling at the cytosolic side of the rough endoplasmic reticulum membranes, in the nucleus, occasionally in mitochondria, and consistently within the fibrillar layer underneath the plasma membrane. Collectively, the data in this model system indicate that hydrogen peroxide, by inhibiting the activation of nuclear transcription factor B, prevents iNOS expression, whereas superoxide contributes in a precise pattern of intracellular protein tyrosine nitration.
Received for publication, October 22, 2002
, and in revised form, April 7, 2003.
* This work was supported by National Heart, Lung and Blood Institute Grants HL5800 (to K. K. G.), HL62526 (to S. L. H.), and HL54926 (to H. I.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Recipient of a postdoctoral fellowship from CNPq-Brazil.
|||| To whom correspondence should be addressed: Stokes Research Institute, Children's Hospital of Philadelphia, 416D Abramson Research Center, 34th St. and Civic Center Blvd., Philadelphia, PA 19104-4318. Tel.: 215-590-5320; Fax: 215-590-4267; E-mail: ischirop{at}mail.med.upenn.edu.
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