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Cardiovascular Research 2006 70(1):136-145; doi:10.1016/j.cardiores.2005.12.018
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Copyright © 2006, European Society of Cardiology

Contribution of serum response factor and myocardin to transcriptional regulation of smoothelins

Sander S.M. Rensena, Petra M.G. Niessena, Xiaochun Longc, Pieter A. Doevendansb, Joseph M. Mianoc and Guillaume J.J.M. van Eysa,*

aDepartment of Genetics and Cell Biology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands
bDepartment of Cardiology, Heart Lung Center Utrecht, Utrecht, The Netherlands and Interuniversity Cardiology Institute, Utrecht, The Netherlands
cCardiovascular Research Institute, University of Rochester School of Medicine, Rochester, NY, United States

* Corresponding author. University of Maastricht, Department of Genetics and Cell Biology, Universiteitssingel 50, PO Box 616, 6200 MD Maastricht, The Netherlands. Tel.: +31 43 3881355; fax: +31 43 3884149. Email address: g.vaneys{at}gen.unimaas.nl

Objective Smoothelin-A and -B isoforms are highly restricted to contractile smooth muscle cells (SMCs). Serum response factor (SRF) and myocardin are essential for contractile SMC differentiation. We evaluated the contribution of SRF/myocardin to transcriptional regulation of smoothelins.

Methods Rat vascular SMCs were transfected with smoothelin-A and smoothelin-B promoter reporter constructs and promoter activity was analyzed. The effects of mutations in the smoothelin-A promoter CArG-boxes and co-transfections with a myocardin expression plasmid were assessed. Electrophoretic mobility shift assays and chromatin immunoprecipitations were performed to investigate SRF-binding to the smoothelin-A CArG-boxes.

Results Smoothelin promoter activity was detected in vascular SMCs. Comparative sequence analysis revealed two conserved CArG elements in the smoothelin-A promoter that bind SRF as shown by chromatin immunoprecipitation. The proximal CArG-near bound SRF stronger than CArG-far in gel shift assays. Mutagenesis studies also indicated that CArG-near is more important than CArG-far in regulating smoothelin-A promoter activity. Myocardin augmented smoothelin-A promoter activity 2.5-fold in a CArG-near-dependent manner. In contrast, myocardin had little effect on the smoothelin-B promoter.

Conclusion Smoothelin-A expression is controlled by an intragenic promoter whose activity is, in part, dependent on two CArG boxes that bind SRF. Our data show a role for SRF/myocardin in regulating smoothelin-A whereas the higher smoothelin-B expression appears to be SRF/myocardin-independent.

KEYWORDS Smoothelins; Myocardin; Serum response factor; Smooth muscle cell differentiation; Gene expression

Time for primary review 23 days


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