Combination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension.
Combination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension.
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雷帕霉素和小剂量伊马替尼联合治疗肺动脉高压
DOI：
10.3389/fphar.2021.758763
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发表时间：
2021
影响因子：
5.6
通讯作者：
Tang H
中科院分区：
文献类型：
--
作者：
Shi Y;Gu C;Zhao T;Jia Y;Bao C;Luo A;Guo Q;Han Y;Wang J;Black SM;Desai AA;Tang H
理由：人肺动脉平滑肌细胞（hPASMC）增殖和远端迁移的增强都有助于肺血管重塑和肺动脉高压（PAH）抵抗力的逐渐增加。我们之前的研究表明，Rictor 缺失会破坏 mTOR 复合物 2 (mTORC2)，在较长时间内会导致 PASMC 中血小板衍生生长因子受体 (PDGFR) 表达的矛盾上升。因此，本研究的目的是评估针对 mTOR 信号传导和 PDGFR 抑制的联合疗法在减弱 PAH 发生和进展方面的作用。方法和结果：免疫印迹分析显示，短期暴露于雷帕霉素（6 小时）显着降低 hPASMC 中 p70S6K（mTORC1 特异性）的磷酸化，但对 AKT（p-AKT S473，被认为是 mTORC2 特异性）的磷酸化没有影响。相反，较长时间的雷帕霉素暴露（> 24 小时）会导致 AKT (T308) 和 AKT (S473) 磷酸化差异，其中 AKT 在 T308 处磷酸化增加，而在 S473 处磷酸化减少。雷帕霉素处理 48 和 72 小时后，hPASMC 中 PDGFRα 和 PDGFRβ 的磷酸化均增加。根据免疫共沉淀研究，较长时间暴露于雷帕霉素（24-72 小时）显着抑制 mTOR 与 Rictor 的结合，从机制上表明雷帕霉素抑制 mTORC2。与单独使用任一药物相比，雷帕霉素与 PDGFR 抑制剂联合暴露，伊马替尼显着降低了 hPASMC 的增殖和迁移。临床前研究证实，雷帕霉素联合伊马替尼在减轻 PAH 方面的疗效优于单独使用任何一种药物。具体而言，联合治疗进一步减弱了大鼠野百合碱（MCT）或缺氧/Sugen诱导的肺动脉高压（PH）的发展，如富尔顿指数、右心室收缩压（RVSP）、肺血管壁厚度和血管肌化的进一步降低以及PASMC中增殖细胞核抗原（PCNA）染色的减少所证明。结论：长期雷帕霉素治疗部分通过 mTORC2 抑制激活 PDGFR 信号传导。雷帕霉素和伊马替尼联合治疗可能是治疗 PAH 的更有效策略。
Rationale: Enhanced proliferation and distal migration of human pulmonary arterial smooth muscle cells (hPASMCs) both contribute to the progressive increases in pulmonary vascular remodeling and resistance in pulmonary arterial hypertension (PAH). Our previous studies revealed that Rictor deletion, to disrupt mTOR Complex 2 (mTORC2), over longer periods result in a paradoxical rise in platelet-derived growth factor receptor (PDGFR) expression in PASMCs. Thus, the purpose of this study was to evaluate the role of combination therapy targeting both mTOR signaling with PDGFR inhibition to attenuate the development and progression of PAH. Methods and Results: Immunoblotting analyses revealed that short-term exposure to rapamycin (6h) significantly reduced phosphorylation of p70S6K (mTORC1-specific) in hPASMCs but had no effect on the phosphorylation of AKT (p-AKT S473, considered mTORC2-specific). In contrast, longer rapamycin exposure (>24 h), resulted in differential AKT (T308) and AKT (S473) phosphorylation with increases in phosphorylation of AKT at T308 and decreased phosphorylation at S473. Phosphorylation of both PDGFRα and PDGFRβ was increased in hPASMCs after treatment with rapamycin for 48 and 72 h. Based on co-immunoprecipitation studies, longer exposure to rapamycin (24–72 h) significantly inhibited the binding of mTOR to Rictor, mechanistically suggesting mTORC2 inhibition by rapamycin. Combined exposure of rapamycin with the PDGFR inhibitor, imatinib significantly reduced the proliferation and migration of hPASMCs compared to either agent alone. Pre-clinical studies validated increased therapeutic efficacy of rapamycin combined with imatinib in attenuating PAH over either drug alone. Specifically, combination therapy further attenuated the development of monocrotaline (MCT)- or Hypoxia/Sugen-induced pulmonary hypertension (PH) in rats as demonstrated by further reductions in the Fulton index, right ventricular systolic pressure (RVSP), pulmonary vascular wall thickness and vessel muscularization, and decreased proliferating cell nuclear antigen (PCNA) staining in PASMCs. Conclusion: Prolonged rapamycin treatment activates PDGFR signaling, in part, via mTORC2 inhibition. Combination therapy with rapamycin and imatinib may be a more effective strategy for the treatment of PAH.
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影响因子：
5.6
作者：
Rol N;Kurakula KB;Happé C;Bogaard HJ;Goumans MJ
通讯作者：
Goumans MJ
影响因子：
--
作者：
Lin J;Huo X;Liu X
通讯作者：
Liu X
DOI：
10.1183/09059180.00007513
发表时间：
2013-12
期刊：
European respiratory review : an official journal of the European Respiratory Society
影响因子：
--
作者：
通讯作者：
--
影响因子：
16
作者：
Sarbassov, DD;Ali, SM;Sabatini, DM
通讯作者：
Sabatini, DM
影响因子：
--
作者：
Jhanwar-Uniyal, Meena;Amin, Anubhav G.;Murali, Raj
通讯作者：
Murali, Raj