H3K9me2 通过 G9a 调控 BDNF 表达参与心力衰竭的进展。
H3K9me2 regulation of BDNF expression via G9a partakes in the progression of heart failure.
机构信息
Department of Cardiac Surgery, Hebei Medical University, Shijiazhuang, 050011, Hebei, People's Republic of China.
Department of Cardiac Surgery, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Xinhua District, Shijiazhuang, 050000, Hebei, People's Republic of China.
出版信息
BMC Cardiovasc Disord. 2022 Apr 19;22(1):182. doi: 10.1186/s12872-022-02621-w.
BACKGROUND
Heart disease is a major cause of mortality in developed countries. The associated pathology is mainly characterized by the loss of cardiomyocytes that contributes to heart failure (HF). This study aims to investigate the mechanism of euchromatic histone lysine methyltransferase 2 (EHMT2, also term G9a) in HF in rats.
METHODS
Differentially expressed mRNAs in HF were screened using GEO database. Sera from subjects with or without HF were collected, and PCR was performed to detect the G9a expression. G9a was downregulated in cardiomyocytes exposed to oxygen-glucose deprivation (OGD), followed by CCK8, flow cytometry, colorimetric method, and western blot assays. Established HF rats were delivered with lentiviral vectors carrying sh-G9a, and TTC staining, HE staining, TUNEL, ELISA, and western blot were performed. The regulation of G9a on the downstream target BDNF was investigated by RT-qPCR, Western blot, and ChIP-qPCR. Finally, rescue experiments were carried out to substantiate the effect of G9a on cardiomyocyte apoptosis and injury via the BDNF/TrkB axis.
RESULTS
G9a was overexpressed, whereas BDNF was downregulated in HF. Knockdown of G9a inhibited apoptosis and injury in OGD-treated cardiomyocytes and attenuated the extent of HF and myocardial injury in rats. Silencing of G9a promoted BDNF transcription by repressing H3K9me2 modification of the BDNF promoter. Further depletion of BDNF partially reversed the effect of sh-G9a in alleviating cardiomyocyte apoptosis and injury by inhibiting the TrkB signaling pathway.
CONCLUSION
G9a inhibits BDNF expression through H3K9me2 modification, thereby impairing the TrkB signaling pathway and exacerbating the development of HF.
背景
心脏病是发达国家主要的死亡原因。相关的病理学主要表现为心肌细胞的丧失，导致心力衰竭（HF）。本研究旨在探讨 euchromatic histone lysine methyltransferase 2（EHMT2，也称为 G9a）在大鼠 HF 中的作用机制。
方法
使用 GEO 数据库筛选 HF 中的差异表达 mRNA。收集有或没有 HF 的受试者的血清，并进行 PCR 检测 G9a 的表达。在暴露于氧葡萄糖剥夺（OGD）的心肌细胞中下调 G9a，然后进行 CCK8、流式细胞术、比色法和 Western blot 检测。向建立的 HF 大鼠递送携带 sh-G9a 的慢病毒载体，并进行 TTC 染色、HE 染色、TUNEL、ELISA 和 Western blot 检测。通过 RT-qPCR、Western blot 和 ChIP-qPCR 研究 G9a 对下游靶标 BDNF 的调控作用。最后，通过 BDNF/TrkB 轴进行 rescue 实验，证实 G9a 对心肌细胞凋亡和损伤的影响。
结果
G9a 在 HF 中过表达，而 BDNF 则下调。G9a 的敲低抑制了 OGD 处理的心肌细胞中的凋亡和损伤，并减轻了 HF 大鼠的 HF 程度和心肌损伤。G9a 的沉默通过抑制 BDNF 启动子的 H3K9me2 修饰促进了 BDNF 的转录。进一步耗尽 BDNF 部分通过抑制 TrkB 信号通路部分逆转了 sh-G9a 减轻心肌细胞凋亡和损伤的作用。
结论
G9a 通过 H3K9me2 修饰抑制 BDNF 的表达，从而损害 TrkB 信号通路并加剧 HF 的发展。
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