FGF21 attenuates hypoxia‑induced dysfunction and apoptosis in HPAECs through alleviating endoplasmic reticulum stress

  • Authors:
    • Ali Chen
    • Jingjing Liu
    • Jianfeng Zhu
    • Xuetao Wang
    • Zhaona Xu
    • Zhimin Cui
    • Dan Yao
    • Zhifeng Huang
    • Min Xu
    • Mayun Chen
    • Peiliang Wu
    • Manxiang Li
    • Liangxing Wang
    • Xiaoying Huang
  • View Affiliations

  • Published online on: May 24, 2018     https://doi.org/10.3892/ijmm.2018.3705
  • Pages: 1684-1694
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Abstract

Vascular endothelial apoptosis and dysfunction have a crucial role in triggering pathological vascular remodeling of hypoxia‑induced pulmonary arterial hypertension (PAH). Fibroblast growth factor (FGF)21, an endocrine regulator, has recently been reported to protect cardiac endothelial cells from damage and suppress inflammatory responses. In addition, FGF21 is reported to be involved in endoplasmic reticulum stress (ERS). Previous studies have suggested that ERS participates in the development of PAH, and attenuation of ERS could be an effective therapeutic strategy for the protection of pulmonary arteries. However, whether FGF21 has a protective function via suppression of ERS in pulmonary arterial endothelial cells in hypoxia remains unclear. The present study aimed to explore whether FGF21 could reduce the hypoxia‑induced apoptosis of human pulmonary arterial endothelial cells (HPAECs) and prevent endothelial dysfunction via the inhibition of ERS. HPAECs were divided into six groups: Normoxia, hypoxia, hypoxia plus FGF21, hypoxia plus salubrinal (an ERS inhibitor), hypoxia plus tunicamycin (an ERS agonist), and hypoxia plus tunicamycin plus FGF21. The endoplasmic reticulum ultrastructure in HPAECs was assessed by transmission electron microscopy, and proliferation and apoptosis were examined by cell counting kit‑8 and terminal deoxyribonucleotide transferase‑mediated dUTP nick end‑labelling assays, respectively. The expression levels of ERS‑related proteins, including binding immunoglobulin protein (BiP), protein kinase R‑like endoplasmic reticulum kinase (PERK), phosphorylated (p‑) PERK, transcription factor C/EBP homologous protein (CHOP), B‑cell lymphoma-2 (Bcl‑2) and caspase‑4 were detected by western blotting. Transwell migration chamber assays were performed, and the concentration of nitric oxide (NO)/endothelin‑1 (ET‑1) in the culture medium was determined to examine endothelial function. The results revealed that hypoxia increased the % of apoptotic cells and diminished the viability of HPAECs, accompanied by an upregulation of ERS‑dependent apoptosis by increasing the expression of the proapoptotic caspase‑4 and decreasing the antiapoptotic Bcl‑2. Additionally, hypoxia upregulated the expression of representative proteins in the PERK branch of ERS, including BiP, p‑PERK and CHOP, while it downregulated the expression of PERK. Furthermore, the secretion of NO/ET‑1 and the migration rate of HPAECs were downregulated under conditions of hypoxia. FGF21 significantly attenuated the hypoxia‑induced apoptosis and dysfunction of HPAECs through alleviating the aforementioned changes in ERS‑dependent signaling pathways. In conclusion, ERS may be a crucial mechanism in the hypoxia‑induced apoptosis and endothelial dysfunction of HPAECs. FGF21 may attenuate the hypoxia‑induced apoptosis and dysfunction of HPAECs through alleviating ERS, via the PERK/CHOP signaling pathway and inhibition of caspase‑4 expression.
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September-2018
Volume 42 Issue 3

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Chen A, Liu J, Zhu J, Wang X, Xu Z, Cui Z, Yao D, Huang Z, Xu M, Chen M, Chen M, et al: FGF21 attenuates hypoxia‑induced dysfunction and apoptosis in HPAECs through alleviating endoplasmic reticulum stress. Int J Mol Med 42: 1684-1694, 2018
APA
Chen, A., Liu, J., Zhu, J., Wang, X., Xu, Z., Cui, Z. ... Huang, X. (2018). FGF21 attenuates hypoxia‑induced dysfunction and apoptosis in HPAECs through alleviating endoplasmic reticulum stress. International Journal of Molecular Medicine, 42, 1684-1694. https://doi.org/10.3892/ijmm.2018.3705
MLA
Chen, A., Liu, J., Zhu, J., Wang, X., Xu, Z., Cui, Z., Yao, D., Huang, Z., Xu, M., Chen, M., Wu, P., Li, M., Wang, L., Huang, X."FGF21 attenuates hypoxia‑induced dysfunction and apoptosis in HPAECs through alleviating endoplasmic reticulum stress". International Journal of Molecular Medicine 42.3 (2018): 1684-1694.
Chicago
Chen, A., Liu, J., Zhu, J., Wang, X., Xu, Z., Cui, Z., Yao, D., Huang, Z., Xu, M., Chen, M., Wu, P., Li, M., Wang, L., Huang, X."FGF21 attenuates hypoxia‑induced dysfunction and apoptosis in HPAECs through alleviating endoplasmic reticulum stress". International Journal of Molecular Medicine 42, no. 3 (2018): 1684-1694. https://doi.org/10.3892/ijmm.2018.3705