Pharmacological Inhibition of mTOR Kinase Reverses Right Ventricle Remodeling and Improves Right Ventricle Structure and Function in Rats
Pharmacological Inhibition of mTOR Kinase Reverses Right Ventricle Remodeling and Improves Right Ventricle Structure and Function in Rats
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DOI：
10.1165/rcmb.2016-0364oc
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发表时间：
2017-11-01
影响因子：
6.4
通讯作者：
Goncharova, Elena A.
中科院分区：
文献类型：
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作者：
Pena, Andressa;Kobir, Ahasanul;Goncharova, Elena A.
肺动脉高压（PAH）的特征是肺血管重塑、肺动脉（PA）压力增加、右心后负荷和死亡。雷帕霉素 (mTOR) 的机制靶点通过两种功能不同的 mTOR 复合物 (mTORC)-1（支持细胞生长）和 -2（促进细胞存活）促进平滑肌细胞增殖、存活和肺血管重塑，而 mTORC1/mTORC2 双重抑制选择性诱导肺动脉高压 PA 血管平滑肌细胞凋亡并逆转肺血管重塑。 mTOR 抑制对右心室 (RV) 形态和功能的影响尚不清楚。使用肺动脉高压（PH）的SU5416/缺氧大鼠模型，我们报告说，与小重塑PA中mTORC1和mTORC2通路的激活相反，RV组织的mTORC1信号传导显着上调，并伴有心肌细胞和RV肥大、RV壁厚度增加、RV/左心室舒张末期面积比、RV收缩性和后负荷（动脉弹性）以及与对照相比，RV 加速时间更短。在 PH 诱导后第 6-8 周，使用 mTOR 激酶抑制剂 PP242 治疗可抑制小 PA 中的 mTORC1 和 mTORC2，但仅抑制 RV 中的 mTORC1 信号传导，从而保留基础 mTORC2-Akt 水平。媒介物治疗的大鼠表现出进一步的 PH 和 RV 恶化以及严重的 RV 纤维化。 PP242逆转肺血管重塑并防止小PA的新生内膜闭塞，显着降低PA压力和肺血管阻力，逆转心肌细胞肥大和RV重塑，改善最大RV收缩力、动脉弹性和RV加速时间，并防止RV纤维化的发展。总的来说，这些数据显示 mTORC1 与 mTORC2 在 RV 病理学中的主要作用，并表明 mTOR 抑制对于同时针对已确定的 PH 中的肺血管重塑和 RV 功能障碍具有潜在吸引力。
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, increased pulmonary artery (PA) pressure, right-heart afterload and death. Mechanistic target of rapamycin (mTOR) promotes smooth muscle cell proliferation, survival, and pulmonary vascular remodeling via two functionally distinct mTOR complexes (mTORCs)-1 (supports cell growth) and -2 (promotes cell survival), and dual mTORC1/mTORC2 inhibition selectively induces pulmonary arterial hypertension PA vascular smooth muscle cell apoptosis and reverses pulmonary vascular remodeling. The consequences of mTOR inhibition on right ventricle (RV) morphology and function are not known. Using SU5416/hypoxia rat model of pulmonary hypertension (PH), we report that, in contrast to activation of both mTORC1 and mTORC2 pathways in small remodeled PAs, RV tissues had predominant up-regulation of mTORC1 signaling accompanied by cardiomyocyte and RV hypertrophy, increased RV wall thickness, RV/left ventricle end-diastolic area ratio, RV contractility and afterload (arterial elastance), and shorter RVacceleration time compared with controls. Treatment with mTOR kinase inhibitor, PP242, at Weeks 6-8 after PH induction suppressed both mTORC1 and mTORC2 in small PAs, but only mTORC1 signaling in RV, preserving basal mTORC2-Akt levels. Vehicle-treated rats showed further PH and RV worsening and profound RV fibrosis. PP242 reversed pulmonary vascular remodeling and prevented neointimal occlusion of small PAs, significantly reduced PA pressure and pulmonary vascular resistance, reversed cardiomyocyte hypertrophy and RV remodeling, improved max RV contractility, arterial elastance, and RV acceleration time, and prevented development of RV fibrosis. Collectively, these data show a predominant role of mTORC1 versus mTORC2 in RV pathology, and suggest potential attractiveness of mTOR inhibition to simultaneously target pulmonary vascular remodeling and RV dysfunction in established PH.