Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension.
Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension.
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DOI：
10.1161/circulationaha.113.004581
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发表时间：
2014-02-25
期刊：
影响因子：
37.8
通讯作者：
Goncharova EA
中科院分区：
文献类型：
--
作者：
Goncharov DA;Kudryashova TV;Ziai H;Ihida-Stansbury K;DeLisser H;Krymskaya VP;Tuder RM;Kawut SM;Goncharova EA
肺动脉血管平滑肌细胞（PAVSMC）增殖增强、抗凋亡和代谢向糖酵解的转变是特发性肺动脉高压（IPAH）肺血管重构的关键病理生理组成部分。不同mTOR复合物mTORC 1（mTOR-raptor）和mTORC 2（mTOR-rictor）在PAH中PAVSMC增殖和存活中的作用及其治疗相关性尚不清楚。免疫组织化学和免疫印迹分析显示，mTORC 1和mTORC 2通路在IPAH受试者的小重塑PA和分离的远端PAVSMC中显著上调，这些受试者的ATP水平、增殖和存活依赖于糖酵解代谢。基于siRNA和药理学的分析表明，虽然mTORC 1和mTORC 2都有助于增殖，但IPAH PAVSMC的ATP产生和存活仅需要mTORC 2。mTORC 2下调能量传感器AMPK，允许mTORC 1-S6活化和增殖增加，以及促凋亡蛋白Bim和IPAH PAVSMC存活的缺陷。Nox 4蛋白水平在IPAH PAVSMC中增加，这是mTORC 2活化、增殖和存活所必需的。在缺氧暴露大鼠的小PA中，在缺氧暴露的第2-28天，Nox 4水平和mTORC 2信号显著上调。在第15-28天用mTOR激酶抑制剂PP 242治疗抑制mTORC 2，但不抑制Nox 4，诱导小PA中的SM特异性凋亡，并逆转大鼠中缺氧诱导的肺血管重构。这些数据提供了一种新的机制联系，即通过能量传感器AMPK Nox 4依赖性激活mTORC 2，以增加PAH中PAVSMC的增殖和存活，这表明了一种新的潜在治疗干预途径。
Enhanced proliferation, resistance to apoptosis and metabolic shift to glycolysis of pulmonary arterial vascular smooth muscle cells (PAVSMC) are key pathophysiological components of pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH). The role of distinct mTOR complexes mTORC1 (mTOR-raptor) and mTORC2 (mTOR-rictor) in PAVSMC proliferation and survival in PAH and their therapeutic relevance is unknown. Immunohistochemical and immunoblot analyses revealed that mTORC1 and mTORC2 pathways are markedly up-regulated in small remodeled PAs and isolated distal PAVSMC from IPAH subjects that have increased ATP levels, proliferation and survival that depend on glycolytic metabolism. siRNA- and pharmacological-based analysis showed that while both mTORC1 and mTORC2 contributing to proliferation, only mTORC2 is required for ATP generation and survival of IPAH PAVSMC. mTORC2 down-regulated energy sensor AMPK allowing activation of mTORC1-S6 and increased proliferation, and deficiency of pro-apoptotic protein Bim and IPAH PAVSMC survival. Nox4 protein levels were increased in IPAH PAVSMC that was necessary for mTORC2 activation, proliferation and survival. Nox4 levels and mTORC2 signaling were significantly up-regulated in small PAs from hypoxia-exposed rats at days 2-28 of hypoxia. Treatment with the mTOR kinase inhibitor PP242 at days 15-28 suppressed mTORC2, but not Nox4, induced SM-specific apoptosis in small PAs and reversed hypoxia-induced pulmonary vascular remodeling in rats. These data provide a novel mechanistic link of Nox4-dependent activation of mTORC2 via energy sensor AMPK to increased proliferation and survival of PAVSMC in PAH suggesting a new potential pathway for the therapeutic interventions.