TORward a Molecular Convergence Point in Pulmonary Arterial Hypertension With mTOR.
TORward a Molecular Convergence Point in Pulmonary Arterial Hypertension With mTOR.
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TORward 通过 mTOR 实现肺动脉高压的分子收敛点。
DOI：
10.1016/j.jacbts.2018.08.003
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Wilkins,MartinR
中科院分区：
文献类型：
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作者：
Maron,BradleyA;Wilkins,MartinR
肺动脉高压（PAH）是一种严重的心肺疾病，其特征是影响远端肺小动脉的闭塞性血管病变。历史上认为PAH是一种肺动脉血管收缩增加的疾病，现在清楚的是，PAH的血管重塑要复杂得多。在PAH患者的肺动脉内皮细胞、肺动脉平滑肌细胞（PASMC）、周细胞和外膜成纤维细胞中观察到的关键内源性表型包括纤维化、细胞凋亡抵抗、增殖和糖酵解细胞代谢趋势（1）。即使在单基因亚型（例如BMPR 2突变）中，这些机制之间的相互作用也有助于更广泛的PAH组织表型，特别是丛源性和肥大性血管病变。认识到PAH最终是由于多个重叠的分子途径，导致临床治疗方法的战略转变。事实上，多项证据表明，同时靶向多种不同的信号通路是改善PAH患者结局的最佳方法（2）。尽管取得了这些进展，但PAH仍然是一种对寿命、生活质量和医疗保健支出有重大影响的病态疾病（3）。可以说，13年来PAH的治疗没有取得重大进展。美国食品药品监督管理局批准的14种PAH特异性药物调节相同的3个关键途径，即内皮素-1、前列环素I2和一氧化氮途径，迄今为止，靶向新途径的尝试在早期临床研究中失败率很高。这种失败的一种可能解释与决定PAH内源性表型的信号通路的相互关联性、收敛性和发散性有关（4）。
Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disease that is characterized by an obliterative vasculopathy affecting distal pulmonary arterioles. Historically regarded as a disease of increased pulmonary arterial vasoconstriction, it is now clear that vascular remodeling in PAH is far more complex. Fibrosis, apoptosis resistance, proliferation, and a tendency toward glycolytic cellular metabolism are key endophenotypes observed in pulmonary artery endothelial cells, pulmonary artery smooth muscle cells (PASMCs), pericytes, and adventitial fibroblasts of patients with PAH (1). Even in monogenic subtypes (eg, BMPR2 mutation), interplay between these mechanisms contributes to the wider PAH histopathophenotype, particularly plexogenic and hypertrophic vascular lesions. Realization that PAH is due ultimately to multiple overlapping molecular pathways has led to a strategic shift in the therapeutic approach clinically. Indeed, several lines of evidence suggest that targeting multiple different signaling pathways simultaneously is optimal for improving outcome in patients with PAH (2).Despite these advances, PAH remains a morbid disease with a significant impact on longevity, quality of life, and health care expenditure (3). Arguably, there has been no major progress in the treatment of PAH for 13 years. The 14 PAH-specific drugs approved by the US Food and Drug Administration modulate the same 3 key pathways, namely the endothelin-1, prostacyclin I2, and nitic oxide pathways, and attempts at targeting novel pathways to date have experienced a high failure rate in early-phase clinical studies. One possible explanation for this failure relates to the interrelatedness, convergence, and divergence of signaling pathways that determine PAH endophenotypes (4).