ZIP12 Contributes to Hypoxic Pulmonary Hypertension by Driving Phenotypic Switching of Pulmonary Artery Smooth Muscle Cells.
ZIP12 Contributes to Hypoxic Pulmonary Hypertension by Driving Phenotypic Switching of Pulmonary Artery Smooth Muscle Cells.
复制标题
ZIP12 通过驱动肺动脉平滑肌细胞的表型转换而导致缺氧性肺动脉高压。
DOI：
10.1097/fjc.0000000000001156
复制
发表时间：
2021
影响因子：
3
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Zhu TT;Wang X;Zheng ZJ;Quan JP;Liu YH;Wang YT;Liu TH;Liu X;Wang M;Zhang Z
据报道，ZIP 12是一种质膜锌转运蛋白，其通过增强肺动脉平滑肌细胞（PASMCs）的增殖来促进肺血管重构（PVR）。然而，ZIP 12促进PASMCs增殖的机制仍不完全清楚。PASMCs的增殖易感性表型转换可导致PVR。鉴于缺氧触发PASMCs的表型转换，ZIP 12介导PVR，本研究旨在探讨ZIP 12介导的PASMCs表型转换是否有助于缺氧诱导的PVR。将大鼠暴露于低氧（10% O2）3周诱导PVR，原代培养大鼠PASMCs在低氧（3% O2）条件下培养48 h诱导增殖。采用免疫荧光、定量逆转录-聚合酶链反应和Western blot分析方法检测靶mRNA和蛋白的表达。采用EdU掺入法和3-（4，5-二甲基噻唑-2-基）-5-（3-羧基甲氧基苯基）-2-（4-磺基苯基）-2H-四氮唑法检测PASMCs的增殖。低氧可上调肺动脉和PASMCs中ZIP 12的mRNA和蛋白表达。ZIP 12基因的敲低可抑制低氧诱导的PASMCs表型转换。我们认为HIF-1α/ZIP 12/pERK通路可能是低氧诱导PASMCs表型转换的一种新机制。ZIP 12的治疗靶向可用于治疗PVR。
ZIP12, a plasmalemmal zinc transporter, reportedly promotes pulmonary vascular remodeling (PVR) by enhancing proliferation of pulmonary artery smooth muscle cells (PASMCs). However, the mechanisms of ZIP12 facilitating PASMCs proliferation remain incompletely appreciated. It has been acknowledged that proliferation-predisposing phenotypic switching of PASMCs can lead to PVR. Given that hypoxia triggers phenotypic switching of PASMCs and ZIP12 mediates PVR, this study aims to explore whether ZIP12-mediated phenotypic switching of PASMCs contributes to hypoxia-induced PVR. Rats were exposed to hypoxia (10% O 2) for 3 weeks to induce PVR, and primary rat PASMCs were cultured under hypoxic condition (3% O 2) for 48 hours to induce proliferation. Immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and Western blot analysis were performed to detect the expression of target mRNAs and proteins. EdU incorporation and 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay were conducted to measure the proliferation of PASMCs. Hypoxia upregulated ZIP12 expression (both mRNA and protein) in pulmonary arteries and PASMCs. Knockdown of ZIP12 inhibited phenotypic switching of PASMCs induced by hypoxia. We propose that HIF-1α/ZIP12/pERK pathway could represent a novel mechanism underlying hypoxia-induced phenotypic switching of PASMCs. Therapeutic targeting of ZIP12 could be exploited to treat PVR.