Deacetylation mechanism and potential reversal strategy of long QT syndrome on hERG K+ channel under hypoxia.

Abstract

Clinically, hypoxia is a major risk factor for long QT syndrome (LQTS), which is associated with many diseases, such as myocardial ischemia. LQTS can be caused by the deficiency of hERG, a potassium ion channel that plays a key role in cardiac repolarization. Modifications such as acetylation of histones or non-histone proteins can affect the protein expression. In the present study, we explored the mechanism underlying hypoxia-induced LQTS and a potential reversal strategy. Experiments were performed under hypoxia to determine transcriptional and post-transcriptional expression changes. We used real-time PCR, chromatin immunoprecipitation assay, and western blotting to determine the histones acetylation in the hERG gene and the mechanism. Molecular docking, western blotting, IP, and patch -clamp assay were performed to determine the acetylation and ubiquitination levels of hERG protein and the mechanism. hERG mRNA and protein expression were found to decrease under hypoxia. The histone deacetylation level increased under hypoxia at both H3K27 and H4 of the hERG gene. HDAC1 and HDAC2 are the key enzymes for the mechanism. HDAC6 directly interacts with hERG. The acetylation level of hERG decreased and the ubiquitination level of hERG increased under hypoxia. The inhibitors of HDAC1, HDAC2, and HDAC6 could reverse the reduction of hERG mRNA and hERG protein expression under hypoxia. In conclusion, deacetylation of hERG gene-associated histones and hERG protein might be the mechanisms for LQTS in patients with hypoxia, and the inhibition of HDAC1, HDAC2, and HDAC6 might be a promising reversal strategy for reducing hERG expression under different pathological conditions.

• Authors: Hui Xue, Yuexin Li, Zhengrong Zhao, Jiacheng Ren, Wenting Yu, Fang Wang, Xianghua Li, Jiaxin Li, Qianqian Xia, Yuxin Zhang, Baoxin Li
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1868 Issue 11 Pg. 166487 (11 01 2022) ISSN: 1879-260X [Electronic] Netherlands
• PMID: 35840042 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Ether-A-Go-Go Potassium Channels
• RNA, Messenger

Topics

• Ether-A-Go-Go Potassium Channels (genetics, metabolism)
• Humans
• Hypoxia
• Long QT Syndrome (chemically induced, genetics)
• Molecular Docking Simulation
• RNA, Messenger