Paclitaxel alleviates monocrotaline-induced pulmonary arterial hypertension via inhibition of FoxO1-mediated autophagy
Paclitaxel alleviates monocrotaline-induced pulmonary arterial hypertension via inhibition of FoxO1-mediated autophagy
复制标题
紫杉醇通过抑制 FoxO1 介导的自噬减轻野百合碱诱导的肺动脉高压
DOI：
10.1007/s00210-019-01615-4
复制
发表时间：
2019-05-01
影响因子：
3.6
通讯作者：
Li, Manxiang
中科院分区：
文献类型：
--
作者：
Feng, Wei;Wang, Jian;Li, Manxiang
自噬的激活参与了肺动脉高压（PAH）的发展。最近的研究表明，细胞质叉头盒蛋白O1 （FoxO1）在癌细胞中激活自噬。紫杉醇已被发现可能逆转PAH的进展。然而，fox01在PAH发病机制中的作用以及紫杉醇对自噬的影响尚不清楚。通过大鼠腹腔注射多环芳烃（MCT）产生多环芳烃。采用右心室收缩压（RVSP）、右心室肥厚指数（RV/LV+S）、内侧壁厚度百分比（%MT）检测PAH的发展。苏木精和伊红染色检测肺血管重构。免疫印迹法检测FoxO1蛋白水平、磷酸化水平和细胞核易位，以及LC3A、LC3B和Beclin-1蛋白水平。结果表明，在MCT-PAH大鼠中，尽管FoxO1表达降低，但FoxO1磷酸化水平升高导致大部分FoxO1积聚在细胞质部分。MCT-PAH组自噬也被激活。在培养的大鼠肺动脉平滑肌细胞（PASMCs）中，敲低FoxO1可明显阻断自噬激活，表明细胞质中FoxO1的升高可刺激自噬激活。紫杉醇治疗PAH大鼠，尽管FoxO1表达增加，但FoxO1磷酸化降低，FoxO1核积累增加，从而抑制自噬，最终降低mct诱导的PAH中RVSP、RV/LV+S和%MT的升高。综上所述，紫杉醇通过foxo1介导的自噬抑制抑制肺血管重构，提示紫杉醇可能成为预防和治疗PAH的新型治疗剂。
It has been demonstrated that activation of autophagy is involved in the development of pulmonary arterial hypertension (PAH). Recent studies have shown that cytosolic forkhead box protein O1 (FoxO1) activates autophagy in cancer cells. Paclitaxel has been found to potentially reverse PAH progression. However, the role of FoxO1 and the effects of paclitaxel on autophagy in the pathogenesis of PAH remain unknown. PAH was generated by intraperitoneal injection of monocrotaline (MCT) to rats. The right ventricular systolic pressure (RVSP), the right ventricle hypertrophy index (RV/LV+S), and the percentage of medial wall thickness (%MT) were used to detect the development of PAH. Hematoxylin and eosin staining was performed to measure pulmonary vascular remodeling. The protein level, phosphorylation, and nucleus translocation of FoxO1 and the levels of LC3A, LC3B, and Beclin-1 were examined by immunoblotting. The results showed that in spite of reduced expression of FoxO1, elevated phosphorylation of FoxO1 caused most of FoxO1 accumulating in cytosolic fraction in MCT-PAH rats. Autophagy was also activated in the MCT-PAH group. In cultured rat pulmonary arterial smooth muscle cells (PASMCs), knockdown of FoxO1 markedly blocked autophagy activation, indicating that elevation of cytosolic FoxO1 stimulates autophagy activation. Treatment of PAH rats with paclitaxel reduced FoxO1 phosphorylation and increased FoxO1 nuclear accumulation, despite increased FoxO1 expression, therefore suppressed autophagy, finally reduced elevated RVSP, RV/LV+S, and %MT in MCT-induced PAH. Taken together, paclitaxel inhibits pulmonary vascular remodeling by FoxO1-mediated autophagy suppression, suggesting that paclitaxel might be a novel therapeutic agent for the prevention and treatment of PAH.