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Volume 17, Issue 1
  • ISSN: 1874-4672
  • E-ISSN: 1874-4702
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Abstract

Introduction

The study aimed to investigate the effects of low concentrations of mitochondrial uncouplers in endothelial cells on the CpG dinucleotide methylation of the ICAM1 gene promoter. The excessive inflammatory response in the endothelium is responsible for the development of many cardiovascular diseases. Mitochondria are important regulators of endothelial cell functions. Mild uncoupling of oxidative phosphorylation and respiration in endothelial mitochondria exerts a long lasting anti-inflammatory effect. However, the detailed mechanism of the anti-inflammatory activity of mitochondrial uncouplers remains unclear.We hypothesized that mild mitochondrial uncoupling leads to epigenetic changes in genomic DNA contributing to the anti-inflammatory response.

Methods

We studied the long-term effects of mitochondria-targeted compounds with the uncoupler’s activities: the antioxidant plastoquinonyl-decyl-triphenylphosphonium (SkQ1), dodecyl-triphenylphosphonium (CTPP), and 2,4-dinitrophenol (DNP). The mRNA expression of the intercellular adhesion molecule 1 (ICAM1), a marker of inflammatory activation of endothelial cells, was measured by RT-qPCR. Cytosine methylation in the CpG sites of the ICAM1 gene promoter was estimated by bisulfite sequencing of individual clones.

Results

It was found that downregulation of ICAM1 expression caused by DNP and CTPP was accompanied by an increase in the methylation of CpG sites in the ICAM1 gene promoter. None of the compounds affected intracellular or intramitochondrial ATP levels.

Conclusion

Low concentrations of mitochondrial oxidative phosphorylation uncouplers are able to increase methylation of ICAM1 gene promoter, which corresponds to the observed decrease in the levels of mRNA of this gene. Thus, the change in methylation of the ICAM1 gene promoter may underlie the mechanism of decreased ICAM1 expression caused by mild mitochondrial depolarization. Mitochondrial uncouplers may be exploited as possible therapeutic candidates to treat excessive inflammation in endothelium, by changing the methylation status of genomic DNA.

© 2024 The Author(s). Published by Bentham Science Publisher.
This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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2024-01-01
2024-11-29

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Mitochondria-targeted Uncouplers Decrease Inflammatory Reactions in Endothelial Cells by Enhancing Methylation of the ICAM1 Gene Promoter
Curr Mol Pharmacol 17, e150823219723 (2024); https://doi.org/10.2174/1874467217666230815142556
/content/journals/cmp/10.2174/1874467217666230815142556
/content/journals/cmp/10.2174/1874467217666230815142556
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  • Article Type:     Research Article
Keyword(s): Endothelium; Epigenetics; ICAM1; Inflammation; Mitochondria; Uncouplers of oxidative phosphorylation

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