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Paclitaxel alleviates monocrotaline-induced pulmonary arterial hypertension via inhibition of FoxO1-mediated autophagy

  • Wei Feng
  • Jian Wang
  • Xin Yan
  • Cui Zhai
  • Wenhua Shi
  • Qingting Wang
  • Qianqian Zhang
  • Manxiang LiEmail author
Original Article
  • 58 Downloads

Abstract

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.

Keywords

Paclitaxel FoxO1 Autophagy Pulmonary arterial hypertension 

Notes

Acknowledgments

We thank the National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgery Engineering Research for its support for our study.

Author contribution

The conception and design were proposed by WF and ML. Animal experiments were finished by WF, JW, and CZ. Molecular biology experiments were performed by WF. Data collection and analysis were conducted by WF, XY, and WS. Paper was drafted by WF and reviewed by QW, QZ, and ML. All authors read and approved the manuscript.

Funding information

The present study was supported by the National Natural Science Foundation of China (Grant No. 81670051).

Compliance with ethical standards

All experiments were performed according to the National Institutes of Health guideline and were approved by the Laboratory Animal Care Committee of Xi’an Jiaotong University.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Wei Feng
    • 1
    • 2
    • 3
  • Jian Wang
    • 1
    • 2
    • 3
  • Xin Yan
    • 1
  • Cui Zhai
    • 1
  • Wenhua Shi
    • 1
    • 2
    • 3
  • Qingting Wang
    • 1
    • 2
    • 3
  • Qianqian Zhang
    • 1
  • Manxiang Li
    • 1
    Email author
  1. 1.Department of Respiratory and Critical Care MedicineThe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
  2. 2.National Local Joint Engineering Research Center for Precision Surgery &Regenerative MedicineXi’anChina
  3. 3.Shaanxi Provincial Center Medicifor Regenerativene and Surgery Engineering ResearchXi’anChina

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