Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.
School of Basic Medical Sciences, Lan Zhou University, Lanzhou, Gansu, People's Republic of China.
Radiat Res. 2021 Aug 1;196(2):183-191. doi: 10.1667/RADE-20-00206.1.
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.
电离辐射暴露与心脏纤维化的风险有关；然而，其潜在的分子机制尚不清楚。生长/分化因子 15（GDF15）是成纤维细胞因子，是转化生长因子β超家族的一个分支。下一代测序分析表明，Gdf15 在辐射诱导的纤维化过程中在心外膜成纤维细胞中增加。然而，Gdf15 在心脏纤维化中的作用仍不清楚。在这项研究中，我们证明了 GDF15 在新生大鼠心脏成纤维细胞和照射后的成年大鼠中的上调表达可诱导纤维化，这通过体外转染 Gdf15 后新生大鼠心脏成纤维细胞的细胞增殖率增加和纤维化标志物（Col1α 和αSMA）的表达增加得到证实。相反，下调 GDF15 抑制心脏纤维化，这通过 G2/M 细胞周期阻滞、抑制细胞增殖和 Col1α 和αSMA 表达水平低得到证实。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 通路促进心脏成纤维细胞纤维化，从而有助于辐射诱导心脏病的发病机制。
