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P2X7 receptor-mediated phenotype switching of pulmonary artery smooth muscle cells in hypoxia

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Abstract

P2X7R activation contributes to the pathogenesis of pulmonary hypertension. However, the molecular mechanism through which P2X7R participates in pulmonary vascular remodeling is largely unknown. The rats and pulmonary artery smooth muscle cells (PASMCs) were maintained under hypoxia. P2X7R expression was determined by real-time PCR and western blotting. The pathological changes of lung tissue were evaluated via HE staining after treatment with a P2X7R antagonist, A740003. After treatment with A740003 or silencing P2X7R, proliferating cell nuclear antigen (PCNA), phenotype markers and phospho-c-Jun N-terminal kinase (JNK)/JNK expression were tested by western blotting. P2X7R expression in hypoxia group was significantly higher than that in normoxia group in vivo and in vitro. The pathological changes of lung tissue induced by hypoxia were significantly relieved by treatment with a P2X7R antagonist, A740003. Hypoxia stimulated the proliferation and synthetic phenotype of PASMCs, which were aggravated by a P2X7R agonist treatment and alleviated by a P2X7R antagonist or silencing P2X7R mRNA treatment. Silencing P2X7R mRNA significantly decreased the hypoxia-induced upregulation of phospho-JNK/JNK in PASMCs. The phenotype switching of PASMCs in hypoxia was reversed by treatment with JNK inhibitor. The findings indicate that P2X7R may be involved in the hypoxia-induced proliferation and phenotype switching of PASMCs via JNK signaling pathway, which suggests a new therapeutic strategy targeting P2X7R in vascular remodeling of pulmonary arterial hypertension.

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Funding

This work was supported by Natural Science Foundation of China (Grant No. 81200011) and Post-doctoral Foundation of Heilongjiang Province (Grant No. LBH-Q15081) and Foundation of Harbin Medical University-Daqing (Grant No. DSJJ2019001).

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  1. Xing Li and Bing Hu have contributed equally to this work.

Authors and Affiliations

  1. Department of Nephrology, The Fifth Affiliated Hospital, Harbin Medical University, 213 Jianshe Road, Kaifa District, Daqing, 163310, Heilongjiang, China

    Xing Li

  2. Department of Anatomy, Harbin Medical University-Daqing, 39 Xinyang Road, Gaoxin District, Daqing, 163319, Heilongjiang, China

    Bing Hu, Li Wang, Qingqing Xia & Xiuqin Ni

  3. Department of Basic Medicine, Science and Technology Education Pioneer Park, Dongsheng District, Ordos, 017099, Inner Mongolia, China

    Bing Hu

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  1. Xing Li
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Correspondence to Xiuqin Ni.

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Li, X., Hu, B., Wang, L. et al. P2X7 receptor-mediated phenotype switching of pulmonary artery smooth muscle cells in hypoxia. Mol Biol Rep 48, 2133–2142 (2021). https://doi.org/10.1007/s11033-021-06222-2

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