title: Hypoxia regulates bone morphogenetic protein signaling through C-terminal-binding protein 1.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Newborn Medicine, Children's Hospital Boston and Harvard Medical School, Boston, Mass. 02115, USA.
authors.forename: Xinqi
authors.initials: X
authors.lastname: Wu
authors.forename: Mun Seog
authors.initials: MS
authors.lastname: Chang
authors.forename: S Alex
authors.initials: SA
authors.lastname: Mitsialis
authors.forename: Stella
authors.initials: S
authors.lastname: Kourembanas
mesh_terms: D000429:Alcohol Oxidoreductases; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology; D000860:Hypoxia / Q000378:metabolism*; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D009243:NAD / Q000032:analysis; D010750:Phosphoproteins / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051798:Inhibitor of Differentiation Protein 1; D010750:Phosphoproteins; D014157:Transcription Factors; D009243:NAD; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D052006:Bone Morphogenetic Protein Receptors, Type II