Editors' ChoiceAtherosclerosis

Turbulent Times for the Atherosclerosis Epigenome

See allHide authors and affiliations

Science Translational Medicine  25 Jun 2014:
Vol. 6, Issue 242, pp. 242ec108
DOI: 10.1126/scitranslmed.3009597

Blood flowing through vessels is typically a smooth process but becomes more turbulent and increases the hemodynamic shear stress at arterial curvatures or branching points and constriction sites. Such stress causes endothelial cells to become dysfunctional and induce atherosclerosis, yet the mechanism for this is unclear. A new study by Dunn et al. reports that disturbed blood flow shifts endothelial gene expression from genes that protect vessels from atherosclerosis (“atheroprotective”) to genes that promote atherosclerosis (“proatherogenic”) by altering genome-wide DNA methylation patterns.

DNA methylation at the 5ʹ carbon of CG dinucleotides is a stable epigenetic modification that can regulate gene expression when it occurs at particular sites, such as promoter regions. DNA methylation has been associated with the pathogenesis of many complex diseases, but its role in atherosclerosis is understudied. In the current study, partial carotid artery ligation was used to introduce laminar blood-flow shear stress. This caused an apparently mechanosensitive regulation of DNA methyl transferase-1 (DNMT1), which is responsible for genome-wide methylation pattern changes in endothelial cells. Similar observations were also made in the lesser curvature of the aortic arch, which is naturally exposed to disturbed blood flow. Among the 11 mechanosensitive genes, five carried hypermethylated adenosine 3ʹ,5ʹ-monophosphate (cAMP) response elements at their promoters, implying that methylation at these sites can serve as a mechanosensitive switch for gene expression. Suppression of DNMT1 by means of RNA silencing or an inhibitor, 5ʹaza-2ʹdeoxycytidine (5Aza), blocked endothelial inflammation in vitro. In vivo, 5Aza treatment suppressed atherosclerotic lesion formation in both acute and chronic mouse models of atherosclerosis. The results of this study spark an interest in novel therapeutics to alter DNA methylation (epigenetics) in human atherosclerosis—a treatment avenue that is yet unexplored in this disease.

J. Dunn et al., Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis. J. Clin. Invest. 10.1172/JCI74792 (2014). [Abstract]

Navigate This Article