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：
10.1101/850115
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发表时间：
2019-11
期刊：
影响因子：
3.7
通讯作者：
Pranindya Rinastiti;K. Ikeda;Elda Putri Rahardini;K. Miyagawa;N. Tamada;Yuko Kuribayashi;K. Hirata;N. Emoto
中科院分区：
文献类型：
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作者：
Pranindya Rinastiti;K. Ikeda;Elda Putri Rahardini;K. Miyagawa;N. Tamada;Yuko Kuribayashi;K. Hirata;N. Emoto
肺动脉高压是一种进行性肺部疾病，由于随之发生的右心室衰竭而预后不良。肺动脉重构和功能障碍是病理性肺动脉压升高的罪魁祸首，但其潜在的分子机制仍有待阐明。以往的全基因组关联研究显示，具有序列相似性13的家族成员A（FAM 13 A）基因位点与慢性阻塞性肺疾病、肺纤维化等多种肺部疾病有显著相关性，但FAM 13 A是否也参与肺动脉高压的发病机制尚不清楚。在这里，我们确定了FAM 13 A在肺动脉高压的发展中的重要作用。FAM 13 A在缺氧性肺动脉高压模型小鼠肺组织中表达减少。我们发现FAM 13 A在肺血管中表达，尤其是在内皮细胞中。FAM 13 A的遗传缺失加重了暴露于慢性缺氧的小鼠的肺动脉高压，并与恶化的肺动脉重塑相关。从机制上讲，FAM 13 A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细胞向间充质细胞的转化。我们的数据揭示了FAM 13 A在肺动脉高压发展中的保护作用，因此增加和/或保持肺动脉内皮细胞中的FAM 13 A表达是治疗肺动脉高压的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 mouse lungs of hypoxia-induced pulmonary hypertension model. 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 β-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.