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(Circulation Research. 2001;89:26.)
© 2001 American Heart Association, Inc.

Molecular Medicine

Tumor Necrosis Factor- Induces Fibronectin Synthesis in Coronary Artery Smooth Muscle Cells by a Nitric Oxide–Dependent Posttranscriptional Mechanism

Catherine A. E. O’Blenes, Caroline Kinnear, Marlene Rabinovitch

From the Division of Cardiovascular Research, The Hospital for Sick Children and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Correspondence to Dr Marlene Rabinovitch, Division of Cardiovascular Research, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8, Canada. E-mail mr{at}sickkids.on.ca

Abstract

Abstract—Postcardiac transplant coronary arteriopathy is associated with tumor necrosis factor- (TNF-) induction of fibronectin-dependent smooth muscle cell (SMC) migration into the subendothelium, resulting in occlusive neointimal formation. Because expression of inducible nitric oxide synthase (iNOS) is elevated in neointimal formation after transplantation and upregulated in vascular SMCs by TNF-, we investigated whether TNF- induction of fibronectin synthesis in coronary artery (CA) SMCs is mediated by nitric oxide (NO). TNF- caused a dose-dependent increase in reactive oxygen and nitrogen intermediates in CA SMCs (P<0.05). This correlated with increased NO production (P<0.05) and fibronectin synthesis (P<0.05). TNF- induction of fibronectin synthesis was abrogated by the NOS inhibitor N^G-monomethyl-L-arginine (L-NMMA) (P<0.05) or the flavonoid-containing enzyme inhibitor diphenyleneiodonium (DPI) (P<0.05) and reproduced with the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) (P<0.05). Northern blotting showed no effect of TNF- on steady-state fibronectin mRNA levels. TNF- increased expression of light chain 3 (LC-3), a protein shown previously to facilitate fibronectin mRNA translation through its interaction with an adenosine-uracil rich element (ARE) in the 3'-untranslated region of fibronectin mRNA. RNA gel mobility shift and UV cross-linking assays using CA SMC lysates revealed protein binding complexes with radiolabeled oligonucleotide containing the ARE, similar to those generated with recombinant LC-3. One of these complexes increased after TNF- treatment, an effect inhibited with L-NMMA or DPI. These data demonstrate a novel paradigm whereby cytokines regulate mRNA translation of extracellular matrix proteins through NO-dependent modulation of RNA binding protein interaction with mRNA.

Key Words: nitric oxide • fibronectin • translation • atherosclerosis • cardiac transplant

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