University of Pennsylvania Perelman School of Medicine, Translational Research Laboratories, Rm. 1214, 125 South 31st St., Philadelphia, PA 19104, USA.
FASEB J. 2013 May;27(5):1796-807. doi: 10.1096/fj.12-222224. Epub 2013 Jan 25.
Mammalian target of rapamycin (mTOR) is a major regulator of cellular metabolism, proliferation, and survival that is implicated in various proliferative and metabolic diseases, including obesity, type 2 diabetes, hamartoma syndromes, and cancer. Emerging evidence suggests a potential critical role of mTOR signaling in pulmonary vascular remodeling. Remodeling of small pulmonary arteries due to increased proliferation, resistance to apoptosis, and altered metabolism of cells forming the pulmonary vascular wall is a key currently irreversible pathological feature of pulmonary hypertension, a progressive pulmonary vascular disorder with high morbidity and mortality. In addition to rare familial and idiopathic forms, pulmonary hypertension is also a life-threatening complication of several lung diseases associated with hypoxia. This review aims to summarize our current knowledge and recent advances in understanding the role of the mTOR pathway in pulmonary vascular remodeling, with a specific focus on the hypoxia component, a confirmed shared trigger of pulmonary hypertension in lung diseases. We also discuss the emerging role of mTOR as a promising therapeutic target and mTOR inhibitors as potential pharmacological approaches to treat pulmonary vascular remodeling in pulmonary hypertension.
哺乳动物雷帕霉素靶蛋白（mTOR）是细胞代谢、增殖和存活的主要调节剂，与多种增殖性和代谢性疾病有关，包括肥胖症、2 型糖尿病、错构瘤综合征和癌症。新出现的证据表明，mTOR 信号在肺血管重构中可能具有关键作用。由于细胞增殖增加、抗细胞凋亡和肺血管壁细胞代谢改变导致的小型肺血管重构，是肺动脉高压的一个关键的、目前不可逆转的病理特征，肺动脉高压是一种进行性肺血管疾病，发病率和死亡率都很高。除了罕见的家族性和特发性形式外，肺动脉高压也是与缺氧相关的几种肺部疾病的致命并发症。本综述旨在总结我们目前对 mTOR 通路在肺血管重构中的作用的了解和最新进展，特别是关注缺氧成分，这是在肺部疾病中确认的肺动脉高压的共同触发因素。我们还讨论了 mTOR 作为有前途的治疗靶点的新兴作用，以及 mTOR 抑制剂作为治疗肺动脉高压中肺血管重构的潜在药物方法。
