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A20 deficiency leads to angiogenesis of pulmonary artery endothelial cells through stronger NF-?B activation under hypoxia.

ABSTRACT: A20 is a zinc finger protein associated with hypoxia. As chronic hypoxia is responsible for intimal hyperplasia and disordered angiogenesis of pulmonary artery, which are histological hallmarks of pulmonary artery hypertension, we intended to explore the role of A20 in angiogenesis of pulmonary artery endothelial cells (ECs). Here, we found a transient elevation of A20 expression in the lung tissues from hypoxic rats compared with normoxic controls. This rapid enhancement was mainly detected in the endothelium, and similar results were reproduced in vitro. During early hypoxia, genetic inhibition of A20 increased proliferation in pulmonary artery ECs, linking to advanced cell cycle progression as well as microtubule polymerization, and aggravated angiogenic effects including tube formation, cell migration and adhesion molecules expression. In addition, a negative feedback loop between nuclear factor-kappa B and A20 was confirmed. Our findings provide evidence for an adaptive role of A20 against pulmonary artery ECs angiogenesis via nuclear factor-kappa B activation.

SUBMITTER: Li J

PROVIDER: S-EPMC4929300 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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A20 deficiency leads to angiogenesis of pulmonary artery endothelial cells through stronger NF-κB activation under hypoxia.

Li Jing J Zhang Linlin L Zhang Yueming Y Liu Ying Y Zhang Hongyue H Wei Liuping L Shen Tingting T Jiang Chun C Zhu Daling D

Journal of cellular and molecular medicine 20160317 7

A20 is a zinc finger protein associated with hypoxia. As chronic hypoxia is responsible for intimal hyperplasia and disordered angiogenesis of pulmonary artery, which are histological hallmarks of pulmonary artery hypertension, we intended to explore the role of A20 in angiogenesis of pulmonary artery endothelial cells (ECs). Here, we found a transient elevation of A20 expression in the lung tissues from hypoxic rats compared with normoxic controls. This rapid enhancement was mainly detected in ...[more]

PMID: 26991692

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Project description:BackgroundThe 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 resultsPatients 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.ConclusionOur 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.

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A20 deficiency leads to angiogenesis of pulmonary artery endothelial cells through stronger NF-?B activation under hypoxia.

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A20 deficiency leads to angiogenesis of pulmonary artery endothelial cells through stronger NF-κB activation under hypoxia.

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