Abstract
BackgroundEndothelial 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.Main body of the abstractOS 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.ConclusionOverall, 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.
Highlights
Vascular endothelial cells (ECs), which are located in the blood vessel wall and function to prevent vascular leakage and protect vascular vessels, are subjected to hemodynamic forces that can activate mechanotransduction and regulateLee and Chiu Journal of Biomedical Science (2019) 26:56 specific regions of aortic trees, i.e., the inner curvatures of the aortic arch; carotid bifurcations; branch points of the coronary, infrarenal, and femoral arteries; and aorto-renal branches
This review focus on discussing (1) the effects of hemodynamic forces, i.e., oscillatory shear stress (OS) and PS, on modulating the expression and activation of epigenetic factors in ECs and (2) the roles of hemodynamics-modulated epigenetic factors in regulating mechanotransduction, including signaling molecules, transcription factors, and gene expression, involved in atherogenic and atheroprotective signaling in ECs
We identified the roles of class I and class II Histone deacetylase (HDAC) in modulating cellular functions, including proliferation, oxidation, and inflammation, in ECs in response to proatherogenic OS and atheroprotective PS (Fig. 3) [48]
Summary
Vascular endothelial cells (ECs), which are located in the blood vessel wall and function to prevent vascular leakage and protect vascular vessels, are subjected to hemodynamic forces that can activate mechanotransduction and regulateLee and Chiu Journal of Biomedical Science (2019) 26:56 specific regions of aortic trees, i.e., the inner curvatures of the aortic arch; carotid bifurcations; branch points of the coronary, infrarenal, and femoral arteries; and aorto-renal branches. Our studies showed that hemodynamic forces, i.e., pro-atherogenic OS and atheroprotective PS, modulate the expressions or nuclear/ cytosolic shuttling of class I (HDAC-1, − 2, and − 3) and class II (HDAC-5 and -7) HDACs to regulate anti-inflammatory and antioxidant signaling by altering the acetylation of transcription factors, including MEF2 and Nrf-2, in EC nuclei, which affect their transcription activities and the expression of downstream anti-inflammatory KLF-2 and antioxidant NQO1 genes.
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