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 hypoxia in vitro. We show that DHEA decreased HIF-1 alpha accumulation under both "chemical hypoxia" with treatment by the iron chelator deferroxamin and gas hypoxia (1% 02). The mRNA levels of HIF-1 alpha 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-1 alpha degradation were not modified by DHEA treatment. In addition, a synthetic derivative of DHEA, 3 beta-methyl-Delta 5-androsten-17-one (which cannot be metabolized), was as active as DHEA on HIF-1 alpha accumulation, as well as testosterone and 17 beta-estradiol (E-2). In HPASMCcultures under nonnoxia and both types of hypoxia, DHEA gave rise to Delta 5-androstene-3 beta,17 beta-diol (ADIOL) and DHEA-sulfate (DHEA-S). Neither testosterone, nor E-2 were found. In addition, ADIOL, DHEA-S, 7 alpha-hydroxy-DHEA and Delta 4-androstene-3,17-dione were ineffective on HIF-1 alpha accumulation. The effect of DHEA per se reducing HIF-1 alpha accumulation may be relevant to reduced hypoxia effects in pulmonary arterial hypertension. (C) 2007 Elsevier Ltd. All rights reserved.