Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow

Lee, Ding Yu; Lee, Chih I.; Lin, Ting Er; Lim, Seh Hong; Zhou, Jing; Tseng, Ying Chih; Chien, Shu; Chiu, Jeng Jiann

doi:10.1073/pnas.1121214109

Cited by 134 publications

(133 citation statements)

References 24 publications

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“…In the present study, we have demonstrated that KLF-2 is involved in the context of shear-eliciting RARα/miR-10a/ GATA6/VCAM-1 signaling in ECs. In combination with previous results (6,19), our findings advance the notion that PS can induce not only the dissociation of HDAC-5/7 from MEF2 to increase KLF-2 expression, but also the accumulation of RARα and RXRα and their association in EC nuclei to enhance RARα-RARE binding and miR-10a expression, thereby down-regulating GATA6 and VCAM-1 in ECs (Fig. 6).…”

Section: Discussionsupporting

confidence: 74%

“…5G). Our previous study showed high levels of HDACs in ECs in the inner curvature of the AA, but not in the outer curvature of the AA and the TA (6). Taken together, these in vivo results are in agreement with our in vitro findings indicating that EC expression levels of RARα, RXRα, HDACs, miR-10a, GATA6, and VCAM-1 are flow patternspecific to induce proinflammatory and anti-inflammatory responses under OS and PS, respectively.…”

Section: Ps Induction Of Mir-10a Is Regulated By Increased Expressionsupporting

confidence: 81%

“…Epigenetic modulations, including histone modification and RNA-based mechanisms, have been identified to regulate vascular functions (2)(3)(4). Histone deacetylases (HDACs) and microRNAs (miRs) have emerged as two important epigenetic mediators in vascular pathophysiology (2)(3)(4)(5)(6). In previous work, we demonstrated that exposure of ECs to OS induces associations of HDAC-3/5/7 with myocyte enhancer factor-2 (MEF-2) to down-regulate the antiinflammatory gene Krüppel-like factor-2 (KLF-2).…”

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confidence: 99%

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MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases

Lee

Lin

Lee

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Histone deacetylases (HDACs) and microRNAs (miRs) have emerged as two important epigenetic factors in the regulation of vascular physiology. This study aimed to elucidate the relationship between HDACs and miRs in the hemodynamic modulation of endothelial cell (EC) dysfunction. We found that miR-10a has the lowest expression among all examined shear-responsive miRs in ECs under oscillatory shear stress (OS), and a relatively high expression under pulsatile shear stress (PS). PS and OS alter EC miR-10a expression to regulate the expression of its direct target GATA6 and downstream vascular cell adhesion molecule (VCAM)-1. PS induces the expression, nuclear accumulation, and association of retinoid acid receptor-α (RARα) and retinoid X receptor-α (RXRα). RARα and RXRα serve as a “director” and an “enhancer,” respectively, to enhance RARα binding to RA-responsive element (RARE) and hence miR-10a expression, thus down-regulating GATA6/VCAM-1 signaling in ECs. In contrast, OS induces associations of “repressors” HDAC-3/5/7 with RARα to inhibit the RARα-directed miR-10a signaling. The flow-mediated miR-10a expression is regulated by Krüppel-like factor 2 through modulation in RARα–RARE binding, with the consequent regulation in GATA6/VCAM-1 in ECs. These results are confirmed in vivo by en face staining on the aortic arch vs. the straight thoracic aorta of rats. Our findings identify a mechanism by which HDACs and RXRα modulate the hormone receptor RARα to switch miR-10a expression and hence the proinflammatory vs. anti-inflammatory responses of vascular endothelium under different hemodynamic forces.

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Section: Discussionsupporting

confidence: 74%

Section: Ps Induction Of Mir-10a Is Regulated By Increased Expressionsupporting

confidence: 81%

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confidence: 99%

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MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases

Lee

Lin

Lee

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…For instance, nuclear factor-like 2 activation by LSS induced the expression of several antioxidative genes, such as heme oxygenase 1 and NAD(P)H quinone oxidoreductase 1, involving phase II detoxification (25,26). In contrast, OSS inhibited nuclear factor-like 2 activity by deacetylation, resulting in decreased expression of heme oxygenase 1 (27). In addition to PXR, constitutive androstane receptor, another xenobiotic nuclear receptor, is also expressed in ECs (28).…”

Section: Discussionmentioning

confidence: 99%

Shear stress activation of nuclear receptor PXR in endothelial detoxification

Wang

Fang

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Endothelial cells (ECs) are constantly exposed to xenobiotics and endobiotics or their metabolites, which perturb EC function, as well as to shear stress, which plays a crucial role in vascular homeostasis. Pregnane X receptor (PXR) is a nuclear receptor and a key regulator of the detoxification of xeno-and endobiotics. Here we show that laminar shear stress (LSS), the atheroprotective flow, activates PXR in ECs, whereas oscillatory shear stress, the atheroprone flow, suppresses PXR. LSS activation of PXR in cultured ECs led to the increased expression of a PXR target gene, multidrug resistance 1 (MDR1). An in vivo study using rats showed that the expression of MDR1 was significantly higher in the endothelium from the descending thoracic aorta, where flow is mostly laminar, than from the inner curvature of aortic arch, where flow is disturbed. Functionally, LSSactivated PXR protects ECs from apoptosis triggered by doxorubicin via the induction of MDR1 and other detoxification genes. PXR also suppressed the expression of proinflammatory adhesion molecules and monocyte adhesion in response to TNF-α and lipopolysaccharide. Overexpression of a constitutively active PXR in rat carotid arteries potently attenuated proinflammatory responses. In addition, cDNA microarray revealed a large number of the PXR-activated endothelial genes whose products are responsible for major steps of detoxification, including phase I and II metabolizing enzymes and transporters. These detoxification genes in ECs are induced by LSS in ECs in a PXR-dependent manner. In conclusion, our results indicate that PXR represents a flow-activated detoxification system to protect ECs against damage by xeno-and endobiotics.hemodynamics | endothelial homeostasis | nuclear hormone receptor | gene regulation

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“…Interestingly, Lee et al 65 have elegantly demonstrated that exposure of HUVEC to OS induces the expression of both class I and II histone deacetylases (HDACs) and their nuclear accumulation in a PI3K/Akt-dependent manner, whereas pulsatile US induced phosphorylation-dependent nuclear export of class II HDACs. Moreover, OS induced the association of HDAC-1/2/3 with Nrf2 and the association of HDAC-3/5/7 with myocyte enhancer factor-2, leading to diminished expression of NQO1 and the transcription factor Klf2.…”

Section: Hypertensionmentioning

confidence: 99%