FosB regulates stretch-induced expression of extracellular matrix proteins in smooth muscle

Aruna Ramachandran, Edward M. Gong, Kristine Pelton, Sandeep A. Ranpura, Michelle Mulone, Abhishek Seth, Pablo Gomez, Rosalyn M. Adam*

*Corresponding author for this work

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Fibroproliferative remodeling in smooth musclerich hollow organs is associated with aberrant extracellular matrix (ECM) production. Although mechanical stimuli regulate ECM protein expression, the transcriptional mediators of this process remain poorly defined. Previously, we implicated AP-1 as a mediator of smooth muscle cell (SMC) mechanotransduction; however, its role in stretch-induced ECM regulation has not been explored. Herein, we identify a novel role for the AP-1 subunit FosB in stretch-induced ECM expression in SMCs. The DNA-binding activity of AP-1 increased after stretch stimulation of SMCs in vitro. In contrast to c-Jun and c-fos, which are also activated by the SMC mitogen platelet-derived growth factor, FosB was only activated by stretch. FosB silencing attenuated the expression of the profibrotic factors tenascin C (TNC) and connective tissue growth factor (CTGF), whereas forced expression of Jun∼FosB stimulated TNC and CTGF promoter activity. Chromatin immunoprecipitation revealed enrichment of AP-1 at the TNC and CTGF promoters. Bladder distension in vivo enhanced nuclear localization of c-jun and FosB. Finally, the distension-induced expression of TNC and CTGF in the detrusor smooth muscle of bladders from wild-type mice was significantly attenuated in FosB-null mice. Together, these findings identify FosB as a mechanosensitive regulator of ECM production in smooth muscle.

Original languageEnglish (US)
Pages (from-to)2977-2989
Number of pages13
JournalAmerican Journal of Pathology
Volume179
Issue number6
DOIs
StatePublished - Dec 2011

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Ramachandran, A., Gong, E. M., Pelton, K., Ranpura, S. A., Mulone, M., Seth, A., Gomez, P., & Adam, R. M. (2011). FosB regulates stretch-induced expression of extracellular matrix proteins in smooth muscle. American Journal of Pathology, 179(6), 2977-2989. https://doi.org/10.1016/j.ajpath.2011.08.034