Epigenetic repression of bone morphogenetic protein receptor II expression in scleroderma
Article first published online: 16 JUL 2013
© 2013 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine
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Journal of Cellular and Molecular Medicine
Volume 17, Issue 10, pages 1291–1299, October 2013
How to Cite
Wang, Y. and Kahaleh, B. (2013), Epigenetic repression of bone morphogenetic protein receptor II expression in scleroderma. Journal of Cellular and Molecular Medicine, 17: 1291–1299. doi: 10.1111/jcmm.12105
- Issue published online: 26 NOV 2013
- Article first published online: 16 JUL 2013
- Manuscript Accepted: 8 JUN 2013
- Manuscript Revised: 21 MAY 2013
- Manuscript Received: 28 JAN 2013
- endothelial cells
Germline mutations in the bone morphogenetic protein type II receptor (BMPRII) gene play an essential role in the pathogenesis of familial pulmonary arterial hypertension (FPAH). In view of the histological similarities between scleroderma (SSc) and FPAH arterial lesion, we examined the expression levels of BMPRII in SSc microvascular endothelial cells (MVEC). Oxidative stress and serum starvation were used to examine apoptotic responses of MVECs. BMPRII expression levels were determined by RT-PCR and by Western blot. Epigenetic regulation of BMPRII expression was examined by the addition of epigenetic inhibitors to MVECs cultures, by methylation-specific PCR, and by sequence analysis of DNA methylation pattern of the BMPRII promotor region. SSc-MVECs were more sensitive to apoptotic signals than were normal-MVECs. A significant decrease in BMPRII expression levels in SSc-MVECs was noted, whereas no significant differences in the expression levels of BMPRIA and BMPRIB were observed. Similar reduction in expression levels was noted in SSc skin biopsies. The expression level of BMPRII in SSc-MVECs was normalized by the addition of 2-deoxy-5-azacytidine and trichostatin A to cell cultures. Extensive CpG sites methylation in the BMPRII promoter region was noted in SSc-MVECs with no detectable site methylation in control-MVECs. SSc-MVECs are more sensitive to apoptotic triggers than are control-MVECs. The enhanced apoptosis may be related to epigenetic repression of BMPRII expression as apoptosis of control-MVECs can be augmented by knocking down BMPRII expression. The role of BMPRII underexpression in the pathogenesis of SSc vasculopathy is suggested and should be investigated further.