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.
journal_name
Circ Resjournal_title
Circulation researchauthors
Wu X,Chang MS,Mitsialis SA,Kourembanas Sdoi
10.1161/01.RES.0000237021.65103.24subject
Has Abstractpub_date
2006-08-04 00:00:00pages
240-7issue
3eissn
0009-7330issn
1524-4571pii
01.RES.0000237021.65103.24journal_volume
99pub_type
杂志文章abstract::Catecholamines and catecholamine-synthesizing enzymes have been examined in specific brain areas during the development of spontaneously (genetic) hypertensive (SH) rats. Changes in catecholamine metabolism were localized to regions of the brain implicated in the regulation of blood pressure. Norepinephrine levels and...
journal_title:Circulation research
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更新日期:1991-10-01 00:00:00
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更新日期:2007-12-07 00:00:00
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更新日期:1990-03-01 00:00:00
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pub_type: 杂志文章,收录出版
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更新日期:1981-02-01 00:00:00
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更新日期:1982-02-01 00:00:00
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doi:10.1161/01.res.76.2.199
更新日期:1995-02-01 00:00:00
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更新日期:1996-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1161/01.RES.0000126848.54740.4A
更新日期:2004-05-14 00:00:00
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pub_type: 杂志文章
doi:10.1161/01.res.65.3.708
更新日期:1989-09-01 00:00:00
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pub_type: 杂志文章
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更新日期:1987-12-01 00:00:00
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pub_type: 杂志文章
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更新日期:1989-06-01 00:00:00
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更新日期:2000-01-07 00:00:00
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更新日期:1994-04-01 00:00:00
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pub_type: 杂志文章
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更新日期:1992-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:1989-11-01 00:00:00
abstract::Phenotypic switching of vascular smooth muscle cells (VSMCs) is known to play a critical role in the development of atherosclerosis. However, the factors present within lesions that mediate VSMC phenotypic switching are unclear. Oxidized phospholipids (OxPLs), including 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosp...
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pub_type: 杂志文章
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更新日期:2009-03-13 00:00:00
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journal_title:Circulation research
pub_type: 杂志文章
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更新日期:2011-02-04 00:00:00
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journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.72.1.137
更新日期:1993-01-01 00:00:00
abstract::The circulatory effects associated with lifelong plasma atrial natriuretic factor (ANF) elevation were examined by generating transgenic mice, which constitutively express a fusion gene consisting of the transthyretin promoter and the ANF structural gene. These mice have chronically elevated ANF levels as compared wit...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.74.4.747
更新日期:1994-04-01 00:00:00
abstract::Urea transporters have been cloned from kidney medulla (UT-A) and erythrocytes (UT-B). We determined whether UT-A proteins could be detected in heart and whether their abundance was altered by uremia or hypertension or in human heart failure. In normal rat heart, bands were detected at 56, 51, and 39 kDa. In uremic ra...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/hh1401.093293
更新日期:2001-07-20 00:00:00