期刊
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
卷 40, 期 5, 页码 1477-1485出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijmm.2017.3140
关键词
fibroblast growth factor 21; apoptosis; endo-plasmic reticulum stress; cardiomyocytes; fibroblast growth factor receptor 1; extracellular signal-regulated kinase 1/2
资金
- National Natural Science Foundation of China [81571636]
- Natural Science Foundation of Shangdong, China [ZR2015HM058]
- Yantai Project of Science and Technology Development Plan grant [2013WS224, 2015WS021]
- Yantai Yuhuangding Hospital Youth Scientist Research Foundation [201526]
- Research Award Fund for Outstanding Young and Middle-aged Scientists of Shandong Province [BS2013SW043]
Fibroblast growth factor 21 (FGF21), as an endocrine factor, is secreted into circulation by injured cardiomyocytes. Endoplasmic reticulum (ER) stress-induced apoptosis has been proposed as an important pathophysiological mechanism for cardiomyocyte injury. However, whether the enhanced expression of FGF21 in cardiomyocytes is linked to ER stress, and the effect and underlying mechanism of FGF21 on ER stress-induced cardiomyocyte apoptosis remain unclear. In the present study, it was demonstrated that mild ER stress resulted in upregulated expression levels of FGF21 and its main receptors, as a response to cell compensation, at the induction of <= 5 mu M tunicamycin (TM). However, excessive ER stress (TM >= 10 mu M) activated the ER stress-mediated apoptosis signaling pathways, including PKR-like ER kinase (PERK)-eukaryotic translational initiation factor 2 alpha (eIF2 alpha)-activating transcription factor 4 (ATF4)-CCAAT/-enhancer-binding protein homologous protein (CHOP) and inositol-requiring kinase 1 alpha (IRE1 alpha)-c-Jun N-terminal kinases (JNK), as well as inhibited the expression of FGF21 and its primary receptors. In addition, FGF21 overexpression provided protection against ER stress-induced cardiomyocyte injury, as evidenced by increased cell viability and reduced apoptosis. These changes were associated with the inhibition of ER stress-mediated apoptosis signaling pathways, as well as increased phosphorylation of FGFR1 and ERK1/2. However, the protective effects of overexpressed FGF21 were abolished following treatment with FGFR1 and ERK1/2 inhibitors. Thus, mild ER stress may induce the expression of FGF21 and its primary receptors in cardiomyocytes. FGF21 inhibits ER stress-induced cardiomyocyte injury as least in part via the FGFR1-ERK1/2 signaling pathway.
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