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GDF15 Promotes Cardiac Fibrosis and Proliferation of Cardiac Fibroblasts via the MAPK/ERK1/2 Pathway after Irradiation in Rats
Radiation Research ( IF 2.5 ) Pub Date : 2021-05-21 , DOI: 10.1667/rade-20-00206.1
Huan Guo 1, 2, 3 , Xinke Zhao 4, 5 , Haining Li 3 , Kedan Liu 3 , Hugang Jiang 1 , Xiangting Zeng 6 , Juan Chang 1 , Chengxu Ma 7 , Zhaoyuan Fu 1 , Xinfang Lv 1 , Tao Wang 3 , Hongyun Guo 3 , Kai Liu 1, 4 , Haixiang Su 3 , Yingdong Li 1, 2
Affiliation  

Ionizing radiation exposure is associated with a risk of cardiac fibrosis; however, the underlying molecular mechanism remains unclear. Growth/differentiation factor-15 (GDF15), a fibroblast factor, is a divergent member of the transforming growth factor β superfamily. Next-generation sequencing analyses has revealed that Gdf15 is increased in cardiac fibroblasts during radiation-induced fibrosis. However, the role of Gdf15 in cardiac fibrosis remains unclear. In this study, we demonstrated that the upregulated expression of GDF15 in newborn rat cardiac fibroblasts and adult rats after irradiation could induce fibrosis, which was confirmed by the increased cell proliferation rate and the increased expression of fibrosis markers (Col1α and αSMA) in newborn rat cardiac fibroblasts after transfection with Gdf15 in vitro. Conversely, the downregulation of GDF15 inhibited cardiac fibrosis, as confirmed by G2/M-cell cycle arrest, suppression of cell proliferation, and low levels of Col1α and αSMA expression. We also found that suppressing the expression of Gdf15 in cardiac fibroblasts could lead to a decrease in CDK1 and inhibit phosphorylation of ERK1/2. Thus, GDF15 might promote cardiac fibroblast fibrosis through the MAPK/ERK1/2 pathway and thus contribute to the pathogenesis of radiation-induced heart disease.



中文翻译:

GDF15通过MAPK/ERK1/2通路促进大鼠心脏纤维化和心脏成纤维细胞增殖

电离辐射暴露与心脏纤维化的风险有关;然而,潜在的分子机制仍不清楚。生长/分化因子-15 (GDF15) 是一种成纤维细胞因子,是转化生长因子 β 超家族的不同成员。新一代测序分析表明,在辐射诱导的纤维化过程中,心脏成纤维细胞中的Gdf15增加。然而,Gdf15在心脏纤维化中的作用仍不清楚。在本研究中,我们证明了辐照后新生大鼠心脏成纤维细胞和成年大鼠中 GDF15 的上调表达可以诱导纤维化,这通过细胞增殖率增加和纤维化标志物(Col1ααSMA)的表达增加得到证实。)在体外转染Gdf15后的新生大鼠心脏成纤维细胞。相反,GDF15 的下调抑制了心脏纤维化,正如 G 2 /M 细胞周期停滞、细胞增殖抑制以及Col1ααSMA表达水平低所证实的那样。我们还发现抑制心脏成纤维细胞中Gdf15的表达可导致 CDK1 减少并抑制 ERK1/2 的磷酸化。因此,GDF15 可能通过 MAPK/ERK1/2 途径促进心脏成纤维细胞纤维化,从而有助于辐射诱发的心脏病的发病机制。

更新日期:2021-05-21
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