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Epigenetic Mechanism in Regulation of Endothelial Function by Disturbed Flow: Induction of DNA Hypermethylation by DNMT1

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Abstract

There is increasing evidence that epigenetic mechanisms such as changes in DNA methylation and histone modification play an important role in regulating cellular functions in physiological and pathophysiological states. We investigated the effects of hemodynamic force disturbance, one of the risk factors for atherogenesis, on DNA methylation in HUVECs and rat carotid arteries. Our results demonstrated that athero-prone oscillatory shear flow (OS) without a clear direction induces DNA hypermethylation in comparison to the athero-protective pulsatile shear flow (PS) with a definite direction. Furthermore, OS increases the expression and nuclear translocation of DNA methyltransferase 1 (DNMT1), which is a major maintenance DNA methyltransferase that adds methyl groups to hemi-methylated DNA to repress gene expression. Pharmacological inhibition of DNMT1 by 5-Aza-2′-deoxycytidine abolished the OS-induced DNA hypermethylation. In vivo experiments also showed increases of DNMT1 expression and DNA methylation in the partially-ligated rat carotid arteries where the shear flow is disturbed. These in vitro and in vivo findings have provided novel evidence of the differential regulation of DNA methylation by different hemodynamic forces acting on vascular endothelium and identified DNMT1 as a key protein that governs the epigenetic changes in response to the pathophysiological stimuli due to disturbed flow.

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Acknowledgments

This study is, in part, supported by NIH fundings HL106579, HL108735, and HL121365 (to S.C.).

Conflict of interest

Jing Zhou, Yi-Shuan Li, Kuei-Chun Wang, and Shu Chien declare that they have no conflicts of interest.

Ethical Standards

No human studies were carried out by the authors for this article.

All animal studies were performed in accordance with National Institutes of Health guidelines and were approved by the UC San Diego IACUC.

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Correspondence to Jing Zhou or Shu Chien.

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Associate Editor Michael R. King oversaw the review of this article.

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Zhou, J., Li, YS., Wang, KC. et al. Epigenetic Mechanism in Regulation of Endothelial Function by Disturbed Flow: Induction of DNA Hypermethylation by DNMT1. Cel. Mol. Bioeng. 7, 218–224 (2014). https://doi.org/10.1007/s12195-014-0325-z

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  • DOI: https://doi.org/10.1007/s12195-014-0325-z

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