A20 attenuates hypoxia-induced pulmonary arterial hypertension by inhibiting NF-κB activation and pulmonary artery smooth muscle cell proliferation

Apr 3, 2020Experimental cell research

A20 may reduce low-oxygen lung artery high blood pressure by blocking inflammation and muscle cell growth

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Abstract

Adenovirus-mediated overexpression of zinc finger protein A20 significantly attenuated the increased right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling in hypoxia-exposed mice.

Zinc finger protein A20 is associated with negative regulation of NF-κB activity.
In chronic hypoxia, the expression of A20 decreases over time in lung tissue.
Overexpression of A20 reduced indicators of pulmonary hypertension, including RVSP and pulmonary vessel muscularization.
Inhibition of A20 negated the protective effects against inflammation and cell proliferation in pulmonary arterial smooth muscle cells.
The results suggest that A20 may block the NF-κB signaling pathway linked to hypoxia-induced pulmonary arterial pressure elevation.

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PAH is a progressive disease characterized by uncontrolled proliferation of PASMCs. Zinc finger protein A20 is a negative feedback regulatory protein of NF-κB activity. The aim of this study was to evaluate zinc finger protein A20 can alleviate PAH in hypoxia exposed mice. C57BL/6 mice received a tail vein injection of adenovirus-mediated ad-A20 and ad-A20 shRNA were exposed to hypoxia. PASMCs isolated from rat pulmonary arteries were cultured in hypoxia, and were transfection of A20 adenovirus. Pulmonary hemodynamic parameters were measured by right heart catheterization. Pulmonary vascular morphological changes were analyzed by HE and α-SMA staining. The expression changes of A20, NF-κB and its downstream protein were detected. The expression of phospho-p65 was increased with the prolongation of hypoxia time. The expression of A20 in lung tissue of chronic hypoxia group decreased with the prolongation of hypoxia time. Adenovirus-mediated A20 (ad-A20) overexpression significantly attenuated the abnormally increased RVSP, RV/(LV + S) ratio, WT%, WA%, α-SMA and the pulmonary vessel muscularization. Ad-A20 treatment markedly attenuated the degradation of phospho-p65 and inhibited the induction of phospho-IκBα induced by hypoxia treatment. Furthermore, silencing A20 abolished the protection by anti-inflammatory activity and the inhibitory effect on cell proliferation. We showed that Zinc finger protein A20 can block NF-κB signaling pathway, alleviates the hypoxia-induced abnormal elevation of pulmonary arterial pressure, hyperproliferation of PASMCs and the pulmonary vascular remodeling.

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A20 attenuates hypoxia-induced pulmonary arterial hypertension by inhibiting NF-κB activation and pulmonary artery smooth muscle cell proliferation

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