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Circulation. 2014 Jul 8;130(2):168-79. doi: 10.1161/CIRCULATIONAHA.113.007690. Epub 2014 Apr 28.

Upregulation of steroidogenic acute regulatory protein by hypoxia stimulates aldosterone synthesis in pulmonary artery endothelial cells to promote pulmonary vascular fibrosis.

Author information

1
From the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA (S.O.V.). bmaron@partners.org.
2
From the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA (S.O.V.).

Abstract

BACKGROUND:

The molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldosteronism correlates positively with vascular remodeling in pulmonary arterial hypertension, suggesting that aldosterone may contribute to the pulmonary vasculopathy of hypoxia. The hypoxia-sensitive transcription factors c-Fos/c-Jun regulate steroidogenic acute regulatory protein (StAR), which facilitates the rate-limiting step of aldosterone steroidogenesis. We hypothesized that c-Fos/c-Jun upregulation by hypoxia activates StAR-dependent aldosterone synthesis in human pulmonary artery endothelial cells (HPAECs) to promote vascular fibrosis in pulmonary arterial hypertension.

METHODS AND RESULTS:

Patients with pulmonary arterial hypertension, rats with Sugen/hypoxia-pulmonary arterial hypertension, and mice exposed to chronic hypoxia expressed increased StAR in remodeled pulmonary arterioles, providing a basis for investigating hypoxia-StAR signaling in HPAECs. Hypoxia (2.0% FiO2) increased aldosterone levels selectively in HPAECs, which was confirmed by liquid chromatography-mass spectrometry. Increased aldosterone by hypoxia resulted from enhanced c-Fos/c-Jun binding to the proximal activator protein-1 site of the StAR promoter in HPAECs, which increased StAR expression and activity. In HPAECs transfected with StAR-small interfering RNA or treated with the activator protein-1 inhibitor SR-11302 [3-methyl-7-(4-methylphenyl)-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid], hypoxia failed to increase aldosterone, confirming that aldosterone biosynthesis required StAR activation by c-Fos/c-Jun. The functional consequences of aldosterone were confirmed by pharmacological inhibition of the mineralocorticoid receptor with spironolactone or eplerenone, which attenuated hypoxia-induced upregulation of the fibrogenic protein connective tissue growth factor and collagen III in vitro and decreased pulmonary vascular fibrosis to improve pulmonary hypertension in vivo.

CONCLUSION:

Our findings identify autonomous aldosterone synthesis in HPAECs attributable to hypoxia-mediated upregulation of StAR as a novel molecular mechanism that promotes pulmonary vascular remodeling and fibrosis.

KEYWORDS:

aldosterone; cell hypoxia; fibrosis; hypertension, pulmonary

PMID:
25001622
PMCID:
PMC4090713
DOI:
10.1161/CIRCULATIONAHA.113.007690
[Indexed for MEDLINE]
Free PMC Article

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