Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China.
Department of Basic Medicine, The Centre of Functional Experiment Teaching, Harbin Medical University, Harbin, Heilongjiang, China.
J Cell Physiol. 2021 Feb;236(2):1094-1104. doi: 10.1002/jcp.29918. Epub 2020 Jul 13.
Sox4 participates in the progression of embryo development and regulation of apoptosis in tumors. However, the effect and mechanism of Sox4 in myocardial infarction (MI) remains unclear. Therefore, we aimed at examining the role and molecular mechanism of Sox4 in the process of cardiomyocytes apoptosis during MI. The expression of Sox4 were obviously increased both in MI mice and in neonatal mouse cardiomyocytes treated with H O . Overexpression of Sox4 promoted cardiomyocyte apoptosis with or without H O , whereas knocking down of Sox4 alleviated H O -induced apoptosis in cardiomyocytes. Furthermore, silencing Sox4 by AAV-9 carried short hairpin RNA targeting Sox4 (AAV-9-sh-Sox4) markedly decreased cardiac infarct area, imprfoved cardiac dysfunction, and reversed apoptosis in MI mice. Mechanistically, there is a potential Sox4-binding site in the promoter region of Bim, and forced expression of Sox4 significantly promoted Bim expression in cultured cardiomyocytes with or without H O , whereas knocking down of Sox4 inhibited the expression of Bim. Further studies showed that silencing Bim attenuated Sox4-induced apoptosis in cardiomyocytes, indicating that Sox4 promoted cardiomyocytes apoptosis through regulation of Bim expression, which can be used as a potential therapeutic target for MI.
Sox4 参与胚胎发育和肿瘤细胞凋亡的调控。然而，Sox4 在心肌梗死（MI）中的作用及机制尚不清楚。因此，我们旨在研究 Sox4 在 MI 过程中心肌细胞凋亡中的作用及分子机制。Sox4 在 MI 小鼠和 H2O2 处理的新生鼠心肌细胞中的表达明显增加。过表达 Sox4 促进心肌细胞凋亡，无论是否存在 H2O2，而敲低 Sox4 可减轻 H2O2 诱导的心肌细胞凋亡。此外，通过携带 Sox4 短发夹 RNA 的 AAV-9（AAV-9-sh-Sox4）沉默 Sox4 可显著减少心肌梗死小鼠的心肌梗死面积，改善心功能障碍，并逆转 MI 小鼠的细胞凋亡。机制上，Bim 启动子区域存在潜在的 Sox4 结合位点，强制表达 Sox4 可显著促进培养的心肌细胞中 Bim 的表达，无论是否存在 H2O2，而敲低 Sox4 则抑制 Bim 的表达。进一步的研究表明，沉默 Bim 可减轻 Sox4 诱导的心肌细胞凋亡，表明 Sox4 通过调节 Bim 的表达促进心肌细胞凋亡，这可作为 MI 的潜在治疗靶点。
