Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition
Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition
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DOI：
10.1371/journal.pone.0226049
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发表时间：
2020-02-13
期刊：
影响因子：
3.7
通讯作者：
Emoto, Noriaki
中科院分区：
文献类型：
--
作者：
Rinastiti, Pranindya;Ikeda, Koji;Emoto, Noriaki
肺动脉高压是一种进行性肺部疾病，由于随之而来的右心室衰竭，预后不良。肺动脉重塑和功能障碍是肺动脉压病理性升高的罪魁祸首，但其潜在的分子机制仍有待阐明。此前的全基因组关联研究揭示了序列相似性家族13成员A（FAM13A）的遗传位点与慢性阻塞性肺病、肺纤维化等多种肺部疾病之间存在显着相关性；然而FAM13A是否也参与肺动脉高压的发病机制仍不清楚。在这里，我们确定了 FAM13A 在肺动脉高压发展中的重要作用。缺氧诱导的肺动脉高压小鼠的肺部 FAM13A 表达降低。我们发现 FAM13A 在肺血管系统中表达，尤其是在内皮细胞中。 FAM13A 基因缺失会加剧慢性缺氧小鼠的肺动脉高压，并导致肺动脉重塑恶化。从机制上讲，FAM13A 可能通过抑制肺动脉内皮细胞中的 β-连环蛋白信号传导来减缓内皮向间质的转变。我们的数据揭示了 FAM13A 在肺动脉高压发展中的保护作用，因此增加和/或保留肺动脉内皮细胞中 FAM13A 的表达是治疗肺动脉高压的一种有吸引力的治疗策略。
Pulmonary hypertension is a progressive lung disease with poor prognosis due to the consequent right heart ventricular failure. Pulmonary artery remodeling and dysfunction are culprits for pathologically increased pulmonary arterial pressure, but their underlying molecular mechanisms remain to be elucidated. Previous genome-wide association studies revealed a significant correlation between the genetic locus of family with sequence similarity 13, member A (FAM13A) and various lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis; however whether FAM13A is also involved in the pathogenesis of pulmonary hypertension remained unknown. Here, we identified a significant role of FAM13A in the development of pulmonary hypertension. FAM13A expression was reduced in the lungs of mice with hypoxia-induced pulmonary hypertension. We identified that FAM13A was expressed in lung vasculatures, especially in endothelial cells. Genetic loss of FAM13A exacerbated pulmonary hypertension in mice exposed to chronic hypoxia in association with deteriorated pulmonary artery remodeling. Mechanistically, FAM13A decelerated endothelial-to-mesenchymal transition potentially by inhibiting beta-catenin signaling in pulmonary artery endothelial cells. Our data revealed a protective role of FAM13A in the development of pulmonary hypertension, and therefore increasing and/or preserving FAM13A expression in pulmonary artery endothelial cells is an attractive therapeutic strategy for the treatment of pulmonary hypertension.