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Abstract：
Concentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated pulmonary vascular resistance reported in patients with pulmonary arterial hypertension. We identified a differential role of mammalian target of rapamycin (mTOR) complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTOR complex 1 attenuated the development of PH; however, inhibition of mTOR complex 2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors in pulmonary arterial smooth muscle cells, and compromised the therapeutic effect of the mTOR inhibitors on PH. In addition, we describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors and the platelet-derived growth factor receptor inhibitors on PH and right ventricular hypertrophy. The data from this study provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure.
摘要：
据报道，肺动脉平滑肌细胞增殖增强导致的同心肺血管壁增厚是肺动脉高压患者肺血管阻力升高的重要病理原因。我们确定了哺乳动物雷帕霉素靶蛋白（mTOR）复合物1和复合物2，两种功能不同的mTOR复合物，在肺动脉高压（PH）的发展中。mTOR复合物1的抑制减弱了PH的发展；然而，抑制mTOR复合物2引起自发性PH，可能是由于肺动脉平滑肌细胞中血小板衍生生长因子受体的上调，并损害了mTOR抑制剂对PH的治疗效果。此外,我们描述了使用mTOR抑制剂和血小板源性生长因子受体抑制剂联合治疗PH和右心室肥大的有前景的治疗策略.这项研究的数据为开发肺动脉高压和右心衰竭患者的新疗法提供了重要的基于机制的观点。
