© 2002 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Fibronectin signaling stimulates BNP gene transcription by inhibiting neuron-restrictive silencer element-dependent repression
aDepartment of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
bDepartment of Molecular Genetic Research, National Institute for Longevity Science, Obu, Aichi 474-8522, Japan
cCREST, Science and Technology corporation of Japan (JST), Obu, Aichi 474-8522 Japan
* Corresponding author. Tel.: +81-75-751-3180; fax: +81-75-751-4351 yssaito{at}kuhp.kyoto-u.ac.jp
Objective: Brain natriuretic peptide (BNP) is a cardiac hormone mainly synthesized in ventricles and its expression is markedly increased in ventricular hypertrophy that involves the accumulation of extracellular matrix proteins, such as fibronectin (Fn). We recently reported that Fn signaling stimulated BNP secretion accompanied by hypertrophic responses in vitro. Methods: To elucidate the regulatory mechanism for BNP gene transcription, we examined cis-acting elements downstream of Fn signaling in rat ventricular myocytes transfected with either the –1812 human BNP-luciferase reporter gene (–1812hBNP/Luc) or one of several truncated forms. Results: A strong cis-repressor element was identified between –552 and –522 in myocytes plated on uncoated dishes. This region contains a neuron-restrictive silencer element (NRSE)-like element (NRSEBNP) that is 90% homologous with the NRSE consensus sequence. Neuron-restrictive silencer factor (NRSF) is known to bind to NRSE and to silence transcription of genes containing NRSE. Deletion of NRSEBNP and dominant negative NRSF markedly increased the reporter activity in transfected cells, suggesting that the NRSE/NRSF system silences basal BNP gene transcription. When myocytes were cultured on Fn-coated dishes, the reporter activity of –1812hBNP/Luc was increased by
600% compared with that on uncoated dishes. Interestingly, truncation from –552 to –522 reduced the Fn-inducible reporter activity. Moreover, deletion of NRSEBNP and dominant negative NRSF also inhibited the Fn-inducible reporter activity. Electrophoretic mobility shift assays showed that Fn signaling inhibited the binding activity of NRSF to NRSEBNP. Conclusion: These results suggest that Fn-induced BNP up-regulation in rat ventricular myocytes is due to inhibition of NRSEBNP-dependent repression of BNP gene transcription.
KEYWORDS Extracellular matrix; Gene expression; Hypertrophy; Myocytes; Natriuretic peptide
1 Present address: The UBC McDonald Research Laboratories/The iCAPTURE Centre, Department of Pathology and Laboratory Medicine, St. Paul's Hospital/Providence Health Care, University of British Columbia, Vancouver, BC, Canada.
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