Axis inhibition protein 2 deficiency leads to hypoxic pulmonary hypertension through β-catenin signaling pathway

Nie, Xiaowei; Qin, Guo‐Wei; Mao, Wenjun; Wang, Wei; Chang, Yanhua; Dong, Wei; Zhou, Min; Wu, Bo; Chen, Jingyu

doi:10.1097/hjh.0000000000000872

Cited by 10 publications

(3 citation statements)

References 40 publications

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“…␤-Catenin is a dual function protein participating both in cell adhesion, as part of adherens junctions and focal adhesions, and in control of various prosurvival genes as a transcription factor (13). In PASMCs, ␤-catenin has been shown to be increased under hypoxic conditions or in response to growth factors and to modulate proliferative responses (24,27,36,38). Moreover, activation and/or overexpression of ␤-catenin has been associated with development of pulmonary hypertension (16).…”

Section: Discussionmentioning

confidence: 99%

Aquaporin 1-mediated changes in pulmonary arterial smooth muscle cell migration and proliferation involve β-catenin

Xing

Jiang

Lai

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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Exposure to hypoxia induces migration and proliferation of pulmonary arterial smooth muscle cells (PASMCs), leading to vascular remodeling and contributing to the development of hypoxic pulmonary hypertension. The mechanisms controlling PASMC growth and motility are incompletely understood, although aquaporin 1 (AQP1) plays an important role. In tumor, kidney, and stem cells, AQP1 has been shown to interact with β-catenin, a dual function protein that activates the transcription of crucial target genes (i.e., c-Myc and cyclin D1) related to cell migration and proliferation. Thus the goal of this study was to examine mechanisms by which AQP1 mediates PASMC migration and proliferation, with a focus on β-catenin. Using primary rat PASMCs from resistance level pulmonary arteries infected with adenoviral constructs containing green fluorescent protein (control; AdGFP), wild-type AQP1 (AdAQP1), or AQP1 with the COOH-terminal tail deleted (AdAQP1M), we demonstrated that increasing AQP1 expression upregulated β-catenin protein levels and the expression (mRNA and protein) of the known β-catenin targets c-Myc and cyclin D1. In contrast, infection with AdAQP1M had no effect on any of these variables. Using silencing approaches to reduce β-catenin levels prevented both hypoxia- and AQP1-induced migration and proliferation of PASMCs, as well as induction of c-Myc and cyclin D1 by AQP1. Thus our results indicate that elevated AQP1 levels upregulate β-catenin protein levels, via a mechanism requiring the AQP1 COOH-terminal tail, enhancing expression of β-catenin targets and promoting PASMC proliferation and migration.

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Section: Discussionmentioning

confidence: 99%

Aquaporin 1-mediated changes in pulmonary arterial smooth muscle cell migration and proliferation involve β-catenin

Xing

Jiang

Lai

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Tissues were then dehydrated, cleared and embedded in paraffin. The paraffin blocks were cut into 4- µ m-thick sections and used for H&E staining analysis (17). The sections were stained with hematoxylin for 10 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…Primary HPASMCs were isolated from the explanted lungs of patients undergoing transplantation for PAH, and from the PAs of donor lungs. The primary culture of HPASMCs was performed according to a previously published protocol (17). Using a light microscope, the distal PAs were microdissected from lung explant tissues in a dissection dish containing cold PBS.…”

Section: Methodsmentioning

confidence: 99%

Long non‑coding RNA MALAT1 sponges miR‑124‑3p.1/KLF5 to promote pulmonary vascular remodeling and cell cycle progression of pulmonary artery hypertension

Wang

et al. 2019

Int J Mol Med

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Previous studies have demonstrated that long non-coding RNA (lncRNA) is involved in vascular remodeling. The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) lncRNA is associated with the proliferation and migration of vascular smooth muscle and endothelial cells; however, its biological role in pulmonary artery hypertension (PAH) is currently unclear. The aim of the present study was to investigate the post-transcriptional regulation of MALAT1 in human pulmonary artery smooth muscle cells (HPASMCs). The results revealed that MALAT1 expression levels were significantly upregulated in the pulmonary arteries (PAs) and HPASMCs obtained from patients with PAH compared with adjacent normal PA tissues and HPASMCs. Knockdown of MALAT1 suppressed the viability and proliferation of HPASMCs and prevented cells entering the G 0 /G 1 cell cycle phase. MALAT1 overexpression exerted the opposite effects. Bioinformatics analysis predicted complementary binding of hsa-microRNA (miR)-124-3p.1 with the 3′-untranslated region of MALAT1. Luciferase reporter assays and RNA immunoprecipitation experiments demonstrated molecular binding between MALAT1 and hsa-miR-124-3p.1. This resulted in the formation of an RNA-induced silencing complex. In addition, Kruppel-like factor 5 (KLF5) was confirmed to be a target gene of MALAT1/hsa-miR-124-3p.1. MALAT1 silencing did not inhibit the proliferation and migration of HPASMCs following knockdown of hsa-miR-124-3p.1. In addition, MALAT1 knockdown was demonstrated to attenuate the expression of KLF5. Following MALAT1 knockdown, the expression level of KLF5 was rescued by inhibition of hsa-miR-124-3p.1 expression. The results of the current study indicate that the MALAT1/hsa-miR-124-3p.1/KLF5 axis may serve a key role in HPASMCs. In addition, the results contribute to what is known regarding the role of MALAT1 in PAH development and provide a novel theoretical basis for the development of new therapeutic interventions for patients with PAH.

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Sulfur dioxide attenuates hypoxia-induced pulmonary arteriolar remodeling via Dkk1/Wnt signaling pathway

Luo

Hong

Diao

et al. 2018

Biomedicine & Pharmacotherapy

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Axis inhibition protein 2 deficiency leads to hypoxic pulmonary hypertension through β-catenin signaling pathway

Cited by 10 publications

References 40 publications

Aquaporin 1-mediated changes in pulmonary arterial smooth muscle cell migration and proliferation involve β-catenin

Aquaporin 1-mediated changes in pulmonary arterial smooth muscle cell migration and proliferation involve β-catenin

Long non‑coding RNA MALAT1 sponges miR‑124‑3p.1/KLF5 to promote pulmonary vascular remodeling and cell cycle progression of pulmonary artery hypertension

Sulfur dioxide attenuates hypoxia-induced pulmonary arteriolar remodeling via Dkk1/Wnt signaling pathway

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