Hypoxia regulates bone morphogenetic protein signaling through C-terminal-binding protein 1

被引:34
作者
Wu, Xinqi
Chang, Mun Seog
Mitsialis, S. Alex
Kourembanas, Stella
机构
[1] Childrens Hosp, Div Newborn Med, Dept Med, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Boston, MA 02115 USA
关键词
hypoxia; bone morphogenetic protein; C-terminal-binding protein 1; inhibitor of differentiation 1; histone deacetylases; pulmonary hypertension;
D O I
10.1161/01.RES.0000237021.65103.24
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Bone morphogenetic protein receptor 2 (BMPR2) mutations have been linked to familial pulmonary arterial hypertension (PAH), but the molecular pathways leading to this severe pathology remain poorly characterized. We report that hypoxia, a paramount stimulus for the development of pulmonary hypertension, suppresses the expression of inhibitor of differentiation 1 (Id1), a downstream target of the BMPR2 pathway, in human pulmonary artery smooth muscle cells (HPASMC). This attenuation of BMP signaling by hypoxia is conveyed through a repression of the transcriptional activity of the BMP responsive element (BRE) through mechanisms involving the transcriptional corepressor C-terminal-binding protein 1 (CtBP-1) and histone deacetylases (HDACs). Concordantly, overexpression of CtBP-1 suppressed BMP signaling, whereas small interfering RNA against CtBP-1 efficiently enhanced BMP stimulation of Id1 gene expression. Scavengers of reactive oxygen species had no effect on the hypoxic regulation of Id1, but, significantly, enhancement of the intracellular NADH/NAD(+) ratio mimicked the effects of hypoxia. These results indicate that attenuation of BMP signaling can occur through modulation of CtBP-1 activity by hypoxia-induced changes in the NADH/NAD(+) ratio. Our findings, taken in context with the observed prevalence of pulmonary arterial hypertension associated with BMPR2 mutations, define converging molecular pathways that lead to the development of pulmonary hypertension, through either genetic or epigenetic loss of function of components of the BMP signaling pathway.
引用
收藏
页码:240 / 247
页数:8
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