Abstract
The earliest atherosclerotic lesions preferentially develop in arterial regions experienced disturbed blood flow, which induces endothelial expression of pro-atherogenic genes and the subsequent endothelial dysfunction. Our previous study has demonstrated an up-regulation of DNA methyltransferase 1 (DNMT1) and a global hypermethylation in vascular endothelium subjected to disturbed flow. Here, we determined that DNMT1-specific inhibition in arterial wall ameliorates the disturbed flow-induced atherosclerosis through, at least in part, targeting cell cycle regulator cyclin A and connective tissue growth factor (CTGF). We identified the signaling pathways mediating the flow-induction of DNMT1. Inhibition of the mammalian target of rapamycin (mTOR) suppressed the DNMT1 up-regulation both in vitro and in vivo. Together, our results demonstrate that disturbed flow influences endothelial function and induces atherosclerosis in an mTOR/DNMT1-dependent manner. The conclusions obtained from this study might facilitate further evaluation of the epigenetic regulation of endothelial function during the pathological development of atherosclerosis and offer novel prevention and therapeutic targets of this disease.
Highlights
The earliest atherosclerotic lesions typically originate in a nonrandom pattern, developing preferentially at arterial branches and curvatures, where unstable disturbed blood flow is prevalent[1]
Because treatment of static endothelial cell (EC) with non-specific DNA methyltransferase (DNMT) inhibitor 5-Aza suppresses migration and proliferation of the cells, we explored the mediatory role of DNA methyltransferase 1 (DNMT1) in oscillatory shear (OS)-induced endothelial migration and proliferation by silencing DNMT1 with recombinant adenovirus expressing shRNA targeting human DNMT1
Recent studies demonstrated that DNMT1is aberrantly expressed in endothelial cells in response to various stimuli, including atheroprone hemodynamic shear stress[3,8]
Summary
The earliest atherosclerotic lesions typically originate in a nonrandom pattern, developing preferentially at arterial branches and curvatures, where unstable disturbed blood flow is prevalent[1]. Vascular ECs in these regions are exposed to laminar and pulsatile shear stress that induces expressions of atheroprotective genes in the cells[1,2]. The proatherogenic genes that can be induced by application of disturbed flow or OS to ECs include cyclin A (CCNA2)[22,23] and connective tissue growth factor (CTGF)[10,24], those have been found to be highly expressed in atherosclerotic plaques[25,26,27]. In this study we have examined the role of DNMT1-dependent promoter methylation in the flow-regulation of EC cyclin A and CTGF expression as well as the functional consequences. We discovered the mechanotransductive mechanisms of OS-specific up-regulation of DNMT1
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