Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension
Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension
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DOI：
10.1096/fj.201500042
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发表时间：
2016-07-01
期刊：
影响因子：
4.8
通讯作者：
Maron, Bradley A.
中科院分区：
文献类型：
--
作者：
Aghamohammadzadeh, Reza;Zhang, Ying-Yi;Maron, Bradley A.
哺乳动物靶标雷帕霉素复合体1(MTORC1)亚单位Raptor的激活可诱导细胞生长，是Akt的下游靶标。升高的醛固酮水平激活Akt，在肺动脉高压(PAH)中，与肺小动脉增厚相关，这表明醛固酮对mTORC1的调节可能介导了不利的肺血管重构。我们假设，醛固酮-Raptor信号诱导异常的肺动脉平滑肌细胞(PASMC)存活模式，从而促进PAH。SU-5416/HO-PAH大鼠和野百合碱-PAH高醛增多症大鼠重建的肺小动脉表达了较高水平的Raptor靶蛋白p70S6K，为进一步研究人PASMCs的醛固酮-Raptor信号转导机制奠定了基础。醛固酮(10(-9)~10(-7)M)增加Akt/mTOR/Raptor激活p70S6K，增加PASMCs的增殖、存活率和抗凋亡能力。在转染Raptor小干扰RNA或经螺内酯/依普利酮处理的PASMC中，来自PAH患者的醛固酮或肺动脉血浆不能增加p70S6K的激活或诱导细胞在体外存活。由Raptor-Small干扰RNA与螺内酯组成的星胺-单甲氧基聚乙二醇体内治疗对肺小动脉Raptor的抑制效果最佳，在体内可降低2种实验性PAH动物模型的微动脉肌化和肺动脉高压。醛固酮上调mTORC1是控制PASMC存活、促进肥厚性血管重塑和PAH的重要病理生物学机制。
Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10(-9) to 10(-7) M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor-small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro. Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo. Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.