Endothelin-1 (ET-1) is a potent vasoconstrictor and co-mitogen for vascular smooth muscle and is implicated in pulmonary vascular remodeling and the development of pulmonary arterial hypertension. Vascular smooth muscle is an important source of ET-1. Here we demonstrate synergistic induction of preproET-1 message RNA and release of mature peptide by a combination of tumor necrosis factor α (TNFα) and interferon γ (IFNγ) in primary human pulmonary artery smooth muscle cells. This induction was prevented by pretreatment with the histone acetyl-transferase inhibitor anacardic acid. TNFα induced a rapid and prolonged pattern of nuclear factor (NF)-κB p65 subunit activation and binding to the native preproET-1 promoter. In contrast, IFNγ induced a delayed activation of interferon regulatory factor-1 without any effect on NF-κB p65 nuclear localization or consensus DNA binding. However, we found cooperative p65 binding and histone H4 acetylation at distinct B sites in the preproET-1 promoter after stimulation with both TNFα and IFNγ. This was associated with enhanced recruitment of RNA polymerase II to the ATG start site and read-through of the ET-1 coding region. Understanding such mechanisms is crucial in determining the key control points in ET-1 release. This has particular relevance to developing novel treatments targeted at the inflammatory component of pulmonary vascular remodeling.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Wort, S. J., Ito, M., Chou, P. C., Mc Master, S. K., Badiger, R., Jazrawi, E., de Souza, P., Evans, T. W., Mitchell, J. A., Pinhu, L., Ito, K., & Adcock, I. M. (2009). Synergistic induction of endothelin-1 by tumor necrosis factor α and interferon γ is due to enhanced NF-κB binding and histone acetylation at specific κB sites. Journal of Biological Chemistry, 284(36), 24297-24305. https://doi.org/10.1074/jbc.M109.032524