Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
J Mol Cell Cardiol. 2018 Feb;115:115-129. doi: 10.1016/j.yjmcc.2018.01.006. Epub 2018 Jan 8.
The underlying mechanisms responsible for the cardioprotective effects of riboflavin remain elusive. Current study tested the hypothesis that riboflavin protects injured myocardium via epigenetic modification of LSD1. Here we showed that myocardial injury was attenuated and cardiac function was improved in riboflavin-treated mice with experimental myocardial infarction (MI), while these protective effects of riboflavin could be partly blocked by cotreatment with LSD1 inhibitor. Riboflavin also reduced apoptosis in hypoxic (1% oxygen) H9C2 cell lines. Results of ChIP-seq for H9C2 cells showed that riboflavin activated LSD1, as verified by decreased H3K4me2 levels of target genes. Subsequent LEGO bioinformatics analysis indicated that phospholipid metabolism genes Lpcat2 and Pld1 served as the potential target genes responsible for the LSD1 mediated protective effects. Overexpressions of Lpcat2 and Pld1 aggravated hypoxic injury in H9C2 cells, while these detrimental effects could be attenuated by overexpression of LSD1. We thus propose that riboflavin alleviates myocardial hypoxic/ischemic injury by activating LSD1 cellular activity and modulating the expression of phospholipid metabolism genes. LSD1-mediated crosstalk between phospholipid metabolism and histone methylation might thus be an important mechanism for the cardioprotective effects of riboflavin.
核黄素发挥心脏保护作用的潜在机制仍不清楚。本研究旨在通过 LSD1 的表观遗传修饰来检验核黄素保护损伤心肌的假说。结果表明，在实验性心肌梗死（MI）的小鼠中，核黄素治疗可减轻心肌损伤，改善心脏功能，而 LSD1 抑制剂的共同治疗可部分阻断核黄素的这些保护作用。核黄素还可减少低氧（1%氧气）H9C2 细胞系中的细胞凋亡。H9C2 细胞的 ChIP-seq 结果表明，核黄素激活了 LSD1，这可通过靶基因 H3K4me2 水平降低得到证实。随后的 LEGO 生物信息学分析表明，磷脂代谢基因 Lpcat2 和 Pld1 可能是 LSD1 介导的保护作用的潜在靶基因。Lpcat2 和 Pld1 的过表达加重了 H9C2 细胞的低氧损伤，而过表达 LSD1 则可减轻这些不利影响。因此，我们提出核黄素通过激活 LSD1 细胞活性和调节磷脂代谢基因的表达来减轻心肌缺氧/缺血损伤。LSD1 介导的磷脂代谢和组蛋白甲基化之间的串扰可能是核黄素发挥心脏保护作用的重要机制。
