mTOR Signaling in Pulmonary Vascular Disease: Pathogenic Role and Therapeutic Target.
mTOR Signaling in Pulmonary Vascular Disease: Pathogenic Role and Therapeutic Target.
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DOI：
10.3390/ijms22042144
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发表时间：
2021-02-21
影响因子：
5.6
通讯作者：
Yuan JX
中科院分区：
文献类型：
--
作者：
Babicheva A;Makino A;Yuan JX
肺动脉高压（PAH）是一种无法治愈的进行性和致命性疾病。PAH的确切致病机制复杂且知之甚少，但许多异常表达的基因和调控途径有助于远端肺动脉的持续血管收缩和血管重塑。哺乳动物雷帕霉素靶蛋白（mTOR）是调节细胞增殖、迁移、分化和蛋白质合成的主要信号通路之一。在这里，我们将描述典型的mTOR通路，mTOR复合物1和2之间的结构和功能差异，以及在PAH的发展中与其他重要信号级联的串扰。由于mTOR对肺动脉平滑肌和内皮细胞的增殖、迁移、表型转变和基因调控的贡献，其在肺血管重塑和持续血管收缩中的致病作用将被讨论。尽管在过去的二十年中，我们在阐明PAH的病因和发病机制方面取得了进展，但仍缺乏有效的治疗药物来治疗PAH患者，这代表了显著未满足的临床需求。本文就mTOR信号通路抑制剂治疗肺动脉高压的可能性和治疗潜力作一综述。
Pulmonary arterial hypertension (PAH) is a progressive and fatal disease without a cure. The exact pathogenic mechanisms of PAH are complex and poorly understood, yet a number of abnormally expressed genes and regulatory pathways contribute to sustained vasoconstriction and vascular remodeling of the distal pulmonary arteries. Mammalian target of rapamycin (mTOR) is one of the major signaling pathways implicated in regulating cell proliferation, migration, differentiation, and protein synthesis. Here we will describe the canonical mTOR pathway, structural and functional differences between mTOR complexes 1 and 2, as well as the crosstalk with other important signaling cascades in the development of PAH. The pathogenic role of mTOR in pulmonary vascular remodeling and sustained vasoconstriction due to its contribution to proliferation, migration, phenotypic transition, and gene regulation in pulmonary artery smooth muscle and endothelial cells will be discussed. Despite the progress in our elucidation of the etiology and pathogenesis of PAH over the two last decades, there is a lack of effective therapeutic agents to treat PAH patients representing a significant unmet clinical need. In this review, we will explore the possibility and therapeutic potential to use inhibitors of mTOR signaling cascade to treat PAH.
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