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| KLF4/BNIP3介导的线粒体自噬在FNDC5抵抗阿霉素心肌毒性中的作用* |
| Protective role of FNDC5 against doxorubicin-induced cardiotoxicity via KFL4-BNIP3 signaling pathway* |
| 投稿时间：2020-08-11 修订日期：2020-08-11 |
| DOI： |
| 中文关键词: FNDC5 Krüppel样因子4 线粒体自噬 纤维化 心肌毒性 |
| 英文关键词: FNDC5,Krüppel like factor 4,mitophagy,fibrosis,cardiotoxicity |
| 基金项目:国家自然科学基金(81774415, 81600295, 81600240, 81870216),西京医院学科助推计划项目 (XJZT18MJ14) |
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| 中文摘要: |
| 目的：本研究旨在探究FNDC5(Irisin)是否通过激活KLF4而抑制BNIP3介导的线粒体过度自噬,保护线粒体功能及降低纤维化蛋白的表达,明确其在DOX导致的心肌细胞毒性中的保护作用机制。方法：将分离的心肌成纤维细胞随机进行如下分组：对照组(CON)、FNDC5处理组(FNDC5)、DOX损伤组(DOX)、FNDC5保护组(DOX-FNDC5)、DOX+Scramble siRNA损伤组(DOX-Scramble siRNA)、FNDC5+Scramble siRNA保护组(DOX-FNDC5-Scramble siRNA)、DOX+KLF4 siRNA组(DOX-KLF4 siRNA)、DOX+FNDC5+KLF4 siRNA组(DOX-FNDC5-KLF4 siRNA),并检测ROS生成量、Western Blot检测线粒体功能及心肌成纤维细胞纤维化标志蛋白的表达等试验方法,观察FNDC5处理对DOX诱导的心肌细胞毒性的作用机制。结果：体外研究表明,与CON组细胞相比,DOX处理后可显著抑制ATP生成,而细胞凋亡率显著增加、同时线粒体自噬过度激活(BNIP3、Atg5及LC3的蛋白表达量明显增加)、细胞纤维化标志蛋白(Collagen I、α-SMA)的表达量显著增加,而FNDC5处理后可显著逆转DOX诱导的心肌细胞损伤。进一步的研究证实,FNDC5通过激活KLF4而抑制BNIP3介导的线粒体自噬,保护线粒体功能及降低纤维化。然而,FNDC5对BNIP3介导的线粒体自噬的抑制作用可被KLF4 siRNA部分抵消,细胞纤维化蛋白表达增加。结论：FNDC5通过激活KLF4信号而抑制BNIP3介导的线粒体过度自噬,保护线粒体功能及降低纤维化蛋白的表达,进而缓解DOX导致的心肌细胞毒性。 |
| 英文摘要: |
| Objective: To investigate whether FNDC5 (Irisin) could inhibit BNIP3-mediated mitophagy to protect mitochondrial function and reduce cardiomyocyte fibrotic protein expressions via activating KLF4, and clarify the protective mechanism of irisin against DOX-induced cardiotoxicity. Methods: Cardiac fibroblats (CFs) cells were randomly divided into the following groups: Control group (CON), FNDC5 treatment group (FNDC5), DOX-induced cardiotoxicity group (DOX), FNDC5 protection group (DOX-FNDC5), DOX+Scramble siRNA group (DOX-Scramble siRNA), FNDC5+Scramble siRNA group (DOX-FNDC5-Scramble siRNA), DOX + KLF4 siRNA group (DOX-KLF4 siRNA), DOX + FNDC5 + KLF4 siRNA group (DOX-FNDC5-KLF4 siRNA). Western blot and ROS detection were used to examine the mitochondrial function and cardiomyocyte fibrotic protein levels. TUNEL staining was used to determine the apoptotic rate of CFs cells. Results: Compared with the CON group, DOX treatment significantly decreased ATP content and cell apoptosis rate was increased while the mitophagy was significantly activated manifested by the increased of BNIP3, ATG5 and LC3 protein expressions Furthermore, cardiomyocyte fibrotic protein expressions (collagen I and α-SMA) was significantly increased, while FNDC5 treatment dramatically reversed DOX-induced cardiotoxicity. Our further study confirmed that FNDC5 inhibits BNIP3 mediated mitophagy to protect mitochondrial function and reduce cardiomyocyte fibrotic protein expressions by activating KLF4 signaling. Nevertheless, the protective role of FNDC5 was abolished by KLF4 siRNA treatment. Conclusions: FNDC5 inhibited BNIP3 mediated mitophagy by activating KLF4 signal, and reduced cardiomyocyte fibrotic protein expressions, thus alleviating DOX-induced cardiotoxicity. |
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