title: Epigenetic Mechanism in Regulation of Endothelial Function by Disturbed Flow: Induction of DNA Hypermethylation by DNMT1.
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 vivoexperiments also showed increases of DNMT1 expression and DNA methylation in the partially-ligated rat carotid arteries where the shear flow is disturbed. Thesein vitroandin vivofindings 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.
authors.affiliation: Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Yi-Shuan
authors.initials: YS
authors.lastname: Li
authors.affiliation: Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Kuei-Chun
authors.initials: KC
authors.lastname: Wang
authors.affiliation: Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
keywords: DNA methylation; DNMT1; Endothelial cells; Oscillatory shear flow