H3K9me2 regulation of BDNF expression via G9a partakes in the progression of heart failure

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.