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DNA methyltransferase 1 (DNMT1) suppresses mitophagy and aggravates heart failure via the microRNA-152-3p/ETS1/RhoH axis

Abstract

DNA methyltransferase 1 (DNMT1) shows close link with heart disease. This study aimed to define the role DNMT1 plays in heart failure and determine the underlying mechanism. Expression of microRNA (miR)-152-3p, DNMT1, E26 transformation specific-1 (ETS1) and ras homolog gene family member H (RhoH) was determined by RT-qPCR and/or western blot analysis. The interaction between miR-152-3p and ETS1 was predicted and verified. Methylation of the miR-152-3p promoter region was assessed using methylation-specific PCR. H9c2 cells were chosen for in vitro assays to examine the regulatory role of DNMT1 in autophagy and mitophagy with respect to miR-152-3p/ETS1/RhoH. Doxorubicin (DOX)-induced rat models of heart failure were employed for in vivo validation. DNMT1 expression was upregulated in the heart tissues of DOX-induced rats, where it showed an inverse correlation with miR-152-3p expression. Moreover, DNMT1 was shown to enhance methylation of the miR-152-3p promoter region and suppress its expression, leading to inhibition of mitophagy in H9c2 cells. In addition, DNMT1 enhanced expression of ETS1, which further elevated RhoH expression. Moreover, ETS1-elevated RhoH reduced cell viability and promoted autophagy and mitophagy in H9c2 cells upon treatment with DOX. Next, in vivo results demonstrated that depletion of DNMT1 protected rats from heart failure in a miR-152-3p/ETS1/RhoH-dependent manner. Overall, these findings indicate that DNMT1 may inhibit expression of miR-152-3p by promoting the methylation of miR-152-3p and enhancing the expression of ETS1, thereby inducing RHOH transcriptional activation and inhibiting mitochondrial autophagy, ultimately promoting the development of heart failure.

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Fig. 1: DNMT1 is upregulated and miR-152-3p is downregulated in the rat heart failure model, exhibiting an inverse correlation.
Fig. 2: DNMT1 enhances DNA methylation at the miR-152-3p promoter region to inhibit miR-152-3p expression.
Fig. 3: DNMT1 suppresses mitophagy in myoblasts by inhibiting miR-152-3p expression.
Fig. 4: DNMT1 promotes ETS1 expression by suppressing miR-152-3p expression in H9c2 cells.
Fig. 5: ETS1 inhibits mitophagy in myoblasts by promoting expression of ETS1.
Fig. 6: DNMT1 inhibits mitophagy in myoblasts through the miR-152-3p/ETS1/RhoH axis.
Fig. 7: Depletion of DNMT1 protects rats from DOX-induced heart failure through the miR-152-3p/ETS1/RhoH axis.
Fig. 8: Schematic diagram of the mechanism by which DNMT1 affects heart failure.

Data availability

All data generated or analyzed during this study are included in this article [and/or] its supplemental material files. Further enquiries can be directed to the corresponding author.

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Z.J.D., J.Q.Y., and X.Y.G. conceived and designed research. J.Q.Y., N.X., and Y.H. performed experiments. N.X., Y.H., and X.W. analyzed data. C.Z.C. and K.C. interpreted results of experiments. Z.J.D. prepared figures. Z.J.D., N.X., Y.H., and X.W. drafted paper. J.Q.Y., C.Z.C., K.C., and X.Y.G. edited and revised paper. All authors approved final version of paper.

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Correspondence to Xiaoyong Geng.

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The current study was approved by the Animal Ethics Committee of the Third Hospital of Hebei Medical University. We attempted to reduce the suffering of the animal used during the experiments.

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Deng, Z., Yao, J., Xiao, N. et al. DNA methyltransferase 1 (DNMT1) suppresses mitophagy and aggravates heart failure via the microRNA-152-3p/ETS1/RhoH axis. Lab Invest 102, 782–793 (2022). https://doi.org/10.1038/s41374-022-00740-8

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