The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People's Republic of China; Department of Cardiac Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, People's Republic of China; Department of Cardiovascular Surgery, People's Liberation Army General Hospital of Southern Theater Command, Guangzhou, 510170, People's Republic of China.
The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People's Republic of China; Department of Cardiovascular Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People's Republic of China.
Exp Cell Res. 2022 Sep 1;418(1):113228. doi: 10.1016/j.yexcr.2022.113228. Epub 2022 Jun 7.
Cardiac reprogramming has emerged as a novel therapeutic approach to regenerating the damaged heart by directly converting endogenous cardiac fibroblasts (CFs) into induced cardiomyocytes (iCMs). Cardiac reprogramming requires the activation of the cardiogenic transcriptional program in concert with the repression of the fibroblastic transcriptional program. Lysine-specific demethylase 1 (LSD1) plays an instrumental role in many physiological processes such as cell growth, differentiation and metabolism. The epigenetic modifications of histones are essential for the accurate expression of genes in cardiomyocytes and the normal functioning of the heart. However, the effect of LSD1 in regulating the cardiogenic transcriptional program under myocardial ischemia/reperfusion (I/R) injury remains unclear. Thus, mice I/R injury was induced by 4 and 24 h reperfusion after 1-h occlusion of the left anterior descending coronary artery. The primary CFs and CMs were exposed under oxygen and glucose deprivation (OGD) to mimic I/R injury. The expression of LSD1 significantly decreased in I/R injured heart tissue and OGD-injured primary CFs and CM, and methylated histone presented a notable increase in OGD-injured primary CFs. Overexpression of LSD1 inhibited the injury of primary CFs induced by OGD, but showed limited inhibition on injured primary CMs. Under the OGD condition, LSD1 overexpression significantly increased cell viability, decreased cell apoptosis and reactive oxygen species (ROS) production of primary CFs. The expression of core cardiogenic transcription factors and cardiac genes were significantly decreased in OGD injured primary CFs, whereas LSD1 overexpression reversed the decrease of transcription factors and cardiac genes under the OGD condition. In conclusion, the overexpression of LSD1 has a protective role in I/R injury by inhibiting the histone methylation of primary CFs and regulates the expressions of core cardiogenic transcription factors and cardiac genes, which can prove to be a potential approach for direct cardiac reprogramming.
心脏重编程作为一种通过直接将内源性心肌成纤维细胞（CFs）转化为诱导性心肌细胞（iCMs）来再生受损心脏的新治疗方法已经出现。心脏重编程需要激活心肌生成转录程序，同时抑制成纤维细胞转录程序。赖氨酸特异性去甲基酶 1（LSD1）在许多生理过程中发挥着重要作用，如细胞生长、分化和代谢。组蛋白的表观遗传修饰对于心肌细胞中基因的准确表达和心脏的正常功能至关重要。然而，LSD1 在调节心肌缺血/再灌注（I/R）损伤下的心肌生成转录程序中的作用尚不清楚。因此，通过在左前降支冠状动脉闭塞 1 小时后再灌注 4 和 24 小时诱导小鼠 I/R 损伤。将原代 CFs 和 CMs 暴露于缺氧和葡萄糖剥夺（OGD）下，模拟 I/R 损伤。LSD1 的表达在 I/R 损伤的心脏组织和 OGD 损伤的原代 CFs 和 CM 中显著降低，而 OGD 损伤的原代 CFs 中组蛋白的甲基化明显增加。LSD1 的过表达抑制了 OGD 诱导的原代 CFs 损伤，但对损伤的原代 CMs 抑制作用有限。在 OGD 条件下，LSD1 的过表达显著提高了原代 CFs 的细胞活力，降低了细胞凋亡和活性氧（ROS）的产生。OGD 损伤的原代 CFs 中核心心肌生成转录因子和心脏基因的表达显著降低，而过表达 LSD1 可逆转 OGD 条件下转录因子和心脏基因的减少。总之，LSD1 的过表达通过抑制原代 CFs 的组蛋白甲基化在 I/R 损伤中发挥保护作用，并调节核心心肌生成转录因子和心脏基因的表达，这可能为直接心脏重编程提供一种潜在的方法。
