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A20 attenuates hypoxia-induced pulmonary arterial hypertension by inhibiting NF-κB activation and pulmonary artery smooth muscle cell proliferation.
- Source :
-
Experimental cell research [Exp Cell Res] 2020 May 15; Vol. 390 (2), pp. 111982. Date of Electronic Publication: 2020 Mar 28. - Publication Year :
- 2020
-
Abstract
- 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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest to report.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Actins genetics
Actins metabolism
Adenoviridae genetics
Adenoviridae metabolism
Animals
Cell Proliferation
Gene Expression Regulation
Genetic Vectors chemistry
Genetic Vectors metabolism
Hypoxia metabolism
Hypoxia pathology
Male
Mice
Mice, Inbred C57BL
Muscle, Smooth, Vascular metabolism
Muscle, Smooth, Vascular pathology
Myocytes, Smooth Muscle pathology
NF-KappaB Inhibitor alpha genetics
NF-KappaB Inhibitor alpha metabolism
Primary Cell Culture
Pulmonary Arterial Hypertension metabolism
Pulmonary Arterial Hypertension pathology
Pulmonary Artery metabolism
Pulmonary Artery pathology
RNA, Small Interfering genetics
RNA, Small Interfering metabolism
Signal Transduction
Transcription Factor RelA metabolism
Tumor Necrosis Factor alpha-Induced Protein 3 antagonists & inhibitors
Tumor Necrosis Factor alpha-Induced Protein 3 metabolism
Hypoxia genetics
Myocytes, Smooth Muscle metabolism
Pulmonary Arterial Hypertension genetics
Transcription Factor RelA genetics
Tumor Necrosis Factor alpha-Induced Protein 3 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2422
- Volume :
- 390
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Experimental cell research
- Publication Type :
- Academic Journal
- Accession number :
- 32234376
- Full Text :
- https://doi.org/10.1016/j.yexcr.2020.111982