Atherosclerosis and flow: roles of epigenetic modulation in vascular endothelium

Abstract

Background: Endothelial cell (EC) dysfunctions, including turnover enrichment, gap junction disruption, inflammation, and oxidation, play vital roles in the initiation of vascular disorders and atherosclerosis. Hemodynamic forces, i.e., atherprotective pulsatile (PS) and pro-atherogenic oscillatory shear stress (OS), can activate mechanotransduction to modulate EC function and dysfunction. This review summarizes current studies aiming to elucidate the roles of epigenetic factors, i.e., histone deacetylases (HDACs), non-coding RNAs, and DNA methyltransferases (DNMTs), in mechanotransduction to modulate hemodynamics-regulated EC function and dysfunction. OS enhances the expression and nuclear accumulation of class I and class II HDACs to induce EC dysfunction, i.e., proliferation, oxidation, and inflammation, whereas PS induces phosphorylation-dependent nuclear export of class II HDACs to inhibit EC dysfunction. PS induces overexpression of the class III HDAC Sirt1 to enhance nitric oxide (NO) production and prevent EC dysfunction. In addition, hemodynamic forces modulate the expression and acetylation of transcription factors, i.e., retinoic acid receptor α and krüppel-like factor-2, to transcriptionally regulate the expression of microRNAs (miRs). OS-modulated miRs, which stimulate proliferative, pro-inflammatory, and oxidative signaling, promote EC dysfunction, whereas PS-regulated miRs, which induce anti-proliferative, anti-inflammatory, and anti-oxidative signaling, inhibit EC dysfunction. PS also modulates the expression of long non-coding RNAs to influence EC function. i.e., turnover, aligmant, and migration. On the other hand, OS enhances the expression of DNMT-1 and -3a to induce EC dysfunction, i.e., proliferation, inflammation, and NO repression.

Conclusion: Overall, epigenetic factors play vital roles in modulating hemodynamic-directed EC dysfunction and vascular disorders, i.e., atherosclerosis. Understanding the detailed mechanisms through which epigenetic factors regulate hemodynamics-directed EC dysfunction and vascular disorders can help us to elucidate the pathogenic mechanisms of atherosclerosis and develop potential therapeutic strategies for atherosclerosis treatment.

Keywords: DNA methyltransferase; Endothelial cell; Epigenetic factor; Hemodynamic force; Histone deacetylase; Non-coding RNA.

Fig. 1

Distribution of hemodynamic forces, i.e., pro-atherogenic OS and atheroprotective PS, in the aortic trees. Pro-atherogenic OS and atheroprotective PS are two types of hemodynamic forces to affect EC function or dysfunction. Pro-atherogenic OS develops in the atherosclerosis-susceptible regions of aortic tree, e.g., the inner curvatures of aortic arch; carotid bifurcations; branch points of the coronary, infrarenal, and femoral arteries; and aorto-renal branches. In contrast, atheroprotective PS occurs in the atherosclerosis-protective regions of aortic tree, e.g., descending thoracic aorta and distal straight renal artery. The athero-prone regions are labeled in the figure.: pro-atherogenic OS;: atheroprotective PS

Fig. 2

Epigenetic regulation of HDACs, non-coding RNAs, and DNMTs in vascular function and dysfunction. HDACs deacetylate not only the transcriptional factor, but also DNA regions of promoter or enhancer, to repress the expressions of anti-inflammatory or anti-oxidative genes. Proliferative, oxidative, and pro-inflammatory miRs target anti-proliferative, anti-oxidative, and anti-inflammatory mRNAs to drive proliferative, oxidative, and inflammatory signaling, respectively. In contrast, anti-proliferative, anti-oxidative, and anti-inflammatory miRs target the respective mRNAs to drive anti-proliferative, anti-oxidative, and anti-inflammatory signaling, respectively. DNMTs methylate DNA regions of promoter or enhancer to inhibit the expression of anti-inflammatory genes to elicit inflammatory signaling. Ac: acetylation; TF: transcription factor; Me: methylation

Fig. 3

Roles of HDACs in modulating hemodynamics-regulated EC dysfunctions, including proliferation, inflammation, and oxidation. Pro-atherogenic OS induces expression and nuclear accumulation of both class I (HDAC-1, − 2, and -3) and class II HDACs (HDAC-5 and -7). Moreover, OS further enhances the formation of HDAC-1/HDAC-2/HDAC-3 and HDAC-3/HDAC-5/HDAC-7 heterocomplexes to promote proliferation, inflammation, and oxidation. In contrast, atheroprotective PS induces phosphorylation-dependent nuclear export of class II HDACs to decrease HDAC levels in the nucleus to inhibit their effects on proliferation, inflammation, and oxidation. On the other hand, PS induces the expression of Class III (Sirt1) to enhance NO production

Fig. 4

Schematic diagram of regulatory machinery for modulating atherosclerosis. Atheroprotective PS induces the expression, nuclear accumulation, and association of RARα (director) and RXRα (enhancer) to promote RARα/RARE binding and miR-10a expression in ECs. PS-induced miR-10a targets pro-inflammatory transcription factor GATA6 to repress its expression to inhibit downstream VCAM-1 expression. PS-induced RARα/miR-10a signaling elicits anti-inflammatory signaling in ECs. In contrast, pro-atherogenic OS induces the association of RARα with HDAC-3/− 5/− 7 (repressors) to repress RARα-directed miR-10a signaling to induce pro-inflammatory responses in ECs