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Kdm6A Protects Against Hypoxia-Induced Cardiomyocyte Apoptosis via H3K27me3 Demethylation of Ncx Gene

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Abstract

Molecular events involved in acute myocardial infarction (AMI) still remain unclear. A rat AMI model and cardiomyocytes cultured in vitro were used to mimic hypoxic conditions, and the profiles of histone methylation-related gene expression were explored. The demethylase Kdm6a expression was significantly upregulated in the rat AMI model and in hypoxia induction. The apoptosis rate of cardiomyocytes was significantly exacerbated when Kdm6a was knocked down. The expression of the Na+/Ca2+ exchanger (Ncx) was significantly upregulated in cardiomyocytes under hypoxia. Knockdown of Kdm6a downregulated the Ncx expression via enhancing H3K27me3 modification on Ncx gene promoter, and attenuated the intracellular calcium influx ability in cardiomyocytes as a consequence. Kdm6a regulates Ncx expression through reducing the H3K27me3 level on the Ncx promoter or enhancer. This finding provides a basis for further study of Kdm6a as a new regulator for AMI development.

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Funding

This study was supported by the National Natural Science Foundation of China (81700293).

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Author notes

  1. Yu Li and Xin Quan contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Beijing Anzhen Hospital Affiliated to Capital Medical University, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China

    Yu Li, Xialing Li, Yu Pan, Tao Zhang, Zhuo Liang & Yunlong Wang

  2. Department of Echocardiography, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China

    Xin Quan

Authors
  1. Yu Li
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  2. Xin Quan
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  3. Xialing Li
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  5. Tao Zhang
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  6. Zhuo Liang
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  7. Yunlong Wang
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Correspondence to Yunlong Wang.

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The authors declare that they have no conflicts of interest.

Research Involving Human Participants

N/A.

Animal Research Ethical Approval

The use of animals was approved by the Ethics Committees of Beijing Anzhen Hospital Affiliated with the Capital Medical University of China and conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (Publication No. 85-23, revised 1996).

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Associate Editor Joost Sluijter oversaw the review of this article

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Clinical Relevance

1. Increased Kdm6a level may lead to dysregulation of Ncx channel expression and attenuated the intracellular calcium influx ability in AMI progression.

2. Kdm6a might be a novel endogenous trigger of AMI and might be a potential target for the treatment of AMI in clinic.

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Li, Y., Quan, X., Li, X. et al. Kdm6A Protects Against Hypoxia-Induced Cardiomyocyte Apoptosis via H3K27me3 Demethylation of Ncx Gene. J. of Cardiovasc. Trans. Res. 12, 488–495 (2019). https://doi.org/10.1007/s12265-019-09882-5

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  • DOI: https://doi.org/10.1007/s12265-019-09882-5

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