Nicotinamide adenine dinucleotide phosphate oxidase–mediated redox signaling and vascular remodeling by 16α-hydroxyestrone in human pulmonary artery cells

Hood, K. Y., Montezano, A. C., Harvey, A. P., Nilsen, M., MacLean, M. R. and Touyz, R. M. (2016) Nicotinamide adenine dinucleotide phosphate oxidase–mediated redox signaling and vascular remodeling by 16α-hydroxyestrone in human pulmonary artery cells. Hypertension, 68(3), pp. 796-808. (doi:10.1161/HYPERTENSIONAHA.116.07668) (PMID:27402919) (PMCID:PMC4978604)

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Abstract

Estrogen and oxidative stress have been implicated in pulmonary arterial hypertension (PAH). Mechanisms linking these systems are elusive. We hypothesized that estrogen metabolite, 16α-hydroxyestrone (16αOHE1), stimulates nicotinamide adenine dinucleotide phosphate oxidase (Nox)–induced reactive oxygen species (ROS) generation and proliferative responses in human pulmonary artery smooth muscle cells (hPASMCs) and that in PAH aberrant growth signaling promotes vascular remodeling. The pathophysiological significance of estrogen–Nox–dependent processes was studied in female Nox1−/− and Nox4−/− mice with PAH. PASMCs from control subjects (control hPASMCs) and PAH patients (PAH-hPASMCs) were exposed to estrogen and 16αOHE1 in the presence/absence of inhibitors of Nox, cytochrome P450 1B1, and estrogen receptors. Estrogen, through estrogen receptor-α, increased Nox-derived ROS and redox-sensitive growth in hPASMCs, with greater effects in PAH-hPASMCs versus control hPASMCs. Estrogen effects were inhibited by cytochrome P450 1B1 blockade. 16αOHE1 stimulated transient ROS production in hPASMCs, with sustained responses in PAH-hPASMCs. Basal expression of Nox1/Nox4 was potentiated in PAH-hPASMCs. In hPASMCs, 16αOHE1 increased Nox1 expression, stimulated irreversible oxidation of protein tyrosine phosphatases, decreased nuclear factor erythroid–related factor 2 activity and expression of nuclear factor erythroid–related factor 2–regulated antioxidant genes, and promoted proliferation. This was further amplified in PAH-hPASMCs. Nox1−/− but not Nox4−/− mice were protected against PAH and vascular remodeling. Our findings demonstrate that in PAH-hPASMCs, 16αOHE1 stimulates redox-sensitive cell growth primarily through Nox1. Supporting this, in vivo studies exhibited protection against pulmonary hypertension and remodeling in Nox1−/− mice. This study provides new insights through Nox1/ROS and nuclear factor erythroid–related factor 2 whereby 16αOHE1 influences hPASMC function, which when upregulated may contribute to vascular injury in PAH, particularly important in women.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Harvey, Dr Adam and Montezano, Dr Augusto and Harvey, Dr Katie and Nilsen, Mrs Margaret and Touyz, Professor Rhian
Authors: Hood, K. Y., Montezano, A. C., Harvey, A. P., Nilsen, M., MacLean, M. R., and Touyz, R. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Hypertension
Publisher:American Heart Association
ISSN:0194-911X
ISSN (Online):1524-4563
Published Online:11 July 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Hypertension 68(3):792-808
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
607381Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)CH/12/4/29762RI CARDIOVASCULAR & MEDICAL SCIENCES
607382Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)RG/13/7/30099RI CARDIOVASCULAR & MEDICAL SCIENCES
573731Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacLeanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES
573733Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacLeanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES