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

doi:10.3892/ijmm.2018.3705

科研成果详情

题名	FGF21 attenuates hypoxia-induced dysfunction and apoptosis in HPAECs through alleviating endoplasmic reticulum stress
作者	Chen, Ali1; Liu, Jingjing1; Zhu, Jianfeng1; Wang, Xuetao 1; Xu, Zhaona 1; Cui, Zhimin 1; Yao, Dan1; Huang, Zhifeng2; Xu, Min1; Chen, Mayun1; Wu, Peiliang1; Li, Manxiang 3; Wang, Liangxing1; Huang, Xiaoying 1
发表日期	2018-09
发表期刊	INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 影响因子和分区
语种	英语
原始文献类型	Article
关键词	pulmonary arterial hypertension endoplasmic reticulum stress fibroblast growth factor 21 human pulmonary arterial endothelial cells
其他关键词	PULMONARY ARTERIAL-HYPERTENSION ; GROWTH-FACTOR 21 ; UNFOLDED PROTEIN RESPONSE ; SMOOTH-MUSCLE-CELLS ; ER-STRESS ; ENDOTHELIAL-CELLS ; NITRIC-OXIDE ; CROSS-TALK ; EXPRESSION ; PATHWAY
摘要	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.
资助项目	Project of Health Department of Zhejiang Province of China [2016DTA005]; Natural Science Foundation Grants of Zhejiang Province [Y17H010028]; Chinese National Natural Science Foundation Grants [81473406]
出版者	SPANDIDOS PUBL LTD
出版地	ATHENS
ISSN	1107-3756
EISSN	1791-244X
卷号	42 期号:3 页码:1684-1694
DOI	10.3892/ijmm.2018.3705
页数	11
WOS类目	Medicine, Research & Experimental
WOS研究方向	Research & Experimental Medicine
WOS记录号	WOS:000446875200047
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	29845288
SCOPUSEID	2-s2.0-85049576789
通讯作者地址	[Huang, Xiaoying]Division of Pulmonary Medicine,First Affiliated Hospital of Wenzhou Medical University,Key Laboratory of Heart and Lung,1 Nanbaixiang Street,Ouhai, Wenzhou, Zhejiang,325000,China
Scopus学科分类	Genetics
引用统计	被引频次：17[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/3302
专题	附属第一医院药学院（分析测试中心）_生物制药系_生物制药工程
通讯作者	Huang, Xiaoying
作者单位	1.Division of Pulmonary Medicine,First Affiliated Hospital of Wenzhou Medical University,Key Laboratory of Heart and Lung,1 Nanbaixiang Street,Ouhai, Wenzhou, Zhejiang,325000,China; 2.Key Laboratory of Biotechnology and Pharmaceutical Engineering of Zhejiang Province,Wenzhou Medical University,Wenzhou, Zhejiang,325000,China; 3.Department of Respiratory Medicine,First Affiliated Hospital of Xi'an Jiaotong University,Xi'an, Shanxi,710061,China
第一作者单位	附属第一医院
通讯作者单位	附属第一医院
第一作者的第一单位	附属第一医院
推荐引用方式 GB/T 7714	Chen, Ali,Liu, Jingjing,Zhu, Jianfeng,et al. FGF21 attenuates hypoxia-induced dysfunction and apoptosis in HPAECs through alleviating endoplasmic reticulum stress[J]. INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE,2018,42(3):1684-1694.
APA	Chen, Ali., Liu, Jingjing., Zhu, Jianfeng., Wang, Xuetao., Xu, Zhaona., ... & Huang, Xiaoying. (2018). FGF21 attenuates hypoxia-induced dysfunction and apoptosis in HPAECs through alleviating endoplasmic reticulum stress. INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 42(3), 1684-1694.
MLA	Chen, Ali,et al."FGF21 attenuates hypoxia-induced dysfunction and apoptosis in HPAECs through alleviating endoplasmic reticulum stress".INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 42.3(2018):1684-1694.