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DHEA decreases HIF-1α accumulation under hypoxia in human pulmonary artery cells: Potential role in the treatment of pulmonary arterial hypertension
Previous work showed that dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary artery hypertension in rat via targeting smooth muscle cells. In our study, DHEA was tested on human pulmonary arterial smooth muscle cells (HPASMC) to identify its mechanism of action under hypox...
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Published in: | The Journal of steroid biochemistry and molecular biology 2008-03, Vol.109 (1), p.81-89 |
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Main Authors: | , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Previous work showed that dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary artery hypertension in rat via targeting smooth muscle cells. In our study, DHEA was tested on human pulmonary arterial smooth muscle cells (HPASMC) to identify its mechanism of action under hypoxia
in vitro. We show that DHEA decreased HIF-1α accumulation under both “chemical hypoxia” with treatment by the iron chelator deferroxamin and gas hypoxia (1% O
2). The mRNA levels of HIF-1α were unchanged whether or not DHEA was applied under chemical and gas hypoxia, as compared to controls in normoxia, suggesting a post-transcriptional effect of the steroid. Protein levels of prolyl hydroxylases responsible for HIF-1α degradation were not modified by DHEA treatment. In addition, a synthetic derivative of DHEA, 3β-methyl-Δ5-androsten-17-one (which cannot be metabolized), was as active as DHEA on HIF-1α accumulation, as well as testosterone and 17β-estradiol (E
2). In HPASMC cultures under normoxia and both types of hypoxia, DHEA gave rise to Δ5-androstene-3β,17β-diol (ADIOL) and DHEA-sulfate (DHEA-S). Neither testosterone, nor E
2 were found. In addition, ADIOL, DHEA-S, 7α-hydroxy-DHEA and Δ4-androstene-3,17-dione were ineffective on HIF-1α accumulation. The effect of DHEA
per se reducing HIF-1α accumulation may be relevant to reduced hypoxia effects in pulmonary arterial hypertension. |
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ISSN: | 0960-0760 1879-1220 |
DOI: | 10.1016/j.jsbmb.2007.12.001 |