Histone Deacetylase (HDAC) Inhibitors Down-Regulate Endothelial Lineage Commitment of Umbilical Cord Blood Derived Endothelial Progenitor Cells

Iordache, Florin; Buzila, Cosmin; Constantinescu, Andreï; Andrei, Eugen; Maniu, Horia

doi:10.3390/ijms131115074

Cited by 20 publications

(17 citation statements)

References 35 publications

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“…Certain lysine residues of histone are subjected to acetylation and deacetylation and each catalyzed by histone acetyltransferases (HATs) and deacetylases (HDACs), respectively [205, 220]. There are multiple proteins with HAT activity, which are divided into three family groups: GNAT, MYST, and CBP/p300 families.…”

Section: Blood Flow and Epigeneticsmentioning

confidence: 99%

Flow signaling and atherosclerosis

Sandhu

Quintana-Quezada

et al. 2016

Cell. Mol. Life Sci.

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Atherosclerosis rarely develops in the region of arteries exposed to undisturbed flow (u-flow, unidirectional flow). Instead, atherogenesis occurs in the area exposed to disturbed flow (d-flow, multidirectional flow). Based on these general pathohistological observations, u-flow is considered to be atheroprotective, while d-flow is atherogenic. The fact that u-flow and d-flow induce such clearly different biological responses in the wall of large arteries indicates that these two types of flow activate each distinct intracellular signaling cascade in vascular endothelial cells (ECs), which are directly exposed to blood flow. The ability of ECs to differentially respond to the two types of flow provides an opportunity to identify molecular events that lead to endothelial dysfunction and atherosclerosis. In this review, we will focus on various molecular events, which are differentially regulated by these two flow types. We will discuss how various kinases, ER stress, inflammasome, SUMOylation, and DNA methylation play roles in the differential flow response, endothelial dysfunction, and atherosclerosis. We will also discuss the interplay among the molecular events and how they coordinately regulate flow-dependent signaling and cellular responses. It is hoped that clear understanding of the way how the two flow types beget each unique phenotype in ECs will lead us to possible points of intervention against endothelial dysfunction and cardiovascular diseases.

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Section: Blood Flow and Epigeneticsmentioning

confidence: 99%

Flow signaling and atherosclerosis

Sandhu

Quintana-Quezada

et al. 2016

Cell. Mol. Life Sci.

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“…It has been reported previously that stable overexpressed vascular endothelial (VE)‐cadherin increased the protein half‐life of VEGFR‐2 in porcine and bovine endothelial cells . Furthermore, it has been shown that high doses of HDACi reduce the expression of VE‐cadherin and VEGFR‐2 in endothelial progenitor cells . To determine the role of VE‐cadherin in HDACi‐mediated reduction of VEGFR‐2 in HUVECs, we first analysed the effects of TSA on VE‐cadherin protein and mRNA levels.…”

Section: Resultsmentioning

confidence: 99%

“…demonstrated that HDACi inhibited VEGF‐induced VEGFR‐2 mRNA expression in endothelial cells . Furthermore, Iordache et al . found that high doses of HDACi reduced expression of the VEGFR‐2, VE‐cadherin and CD117 in endothelial progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

“…First evidence has demonstrated anti‐angiogenic activities of HDACi by suppression of VEGF‐induced VEGFR‐2 mRNA expression in endothelial cells . Furthermore, it has been found that high doses of HDACi reduced surface expression of VEGFR‐2 in endothelial progenitor cells . However, the underlying molecular mechanisms of HDACi‐mediated inhibition of VEGFR‐2 protein expression in endothelial cells are not fully investigated so far and in part remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Histone deacetylase inhibitors interfere with angiogenesis by decreasing endothelial VEGFR‐2 protein half‐life in part via a VE‐cadherin‐dependent mechanism

Hrgović

Doll

Pinter

et al. 2017

Experimental Dermatology

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Recent evidence suggests that histone deacetylase inhibitors (HDACi) may mediate part of their antitumor effects by interfering with tumor angiogenesis. As signalling via the vascular endothelial growth factor receptor-2 (VEGFR-2) pathway is critical for angiogenic responses during tumor progression, we explored whether established antitumor effects of HDACi are partly mediated through diminished endothelial VEGFR-2 expression. We therefore examined the potential impact of three different HDACi, trichostatin A (TSA), sodium butyrate (But) and valproic acid (VPA), on VEGFR-2 protein expression. TSA, VPA and But significantly inhibit VEGFR-2 protein expression in endothelial cells. Pertinent to these data, VEGFR-2 protein half-life is shown to be decreased in response to HDACi. Recently, it could be demonstrated that expression of VE-cadherin influences VEGFR-2 protein half-life. In our experiments, VEGFR-2 downregulation was accompanied by HDACi-induced VE-cadherin suppression. Interestingly, siRNA-mediated knockdown of VE-cadherin led to a pronounced loss of VEGFR-2 expression on the protein as well as on the mRNA level, implicating that VE-cadherin not only influences VEGFR-2 protein half-life but also the transcriptional level. To further distinguish which of the eight different histone deacetylases are responsible for the regulation of VEGFR-2 expression, specific HDAC genes were silenced by transfecting respective siRNAs. These studies revealed that HDACs 1, 4, 5 and 6 are preferentially involved in VEGFR-2 expression. Therefore, these results provide an explanation for the anti-angiogenic action of HDAC inhibitors via a VE-cadherin, HDAC 1 and HDACs 4-6-mediated suppression of VEGFR-2 expression and might be of importance in the development of new anti-angiogenic drugs.

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“…Histone acetylation is catalyzed by two types of molecules, histone acetyltransferases (HATs) and HDACs (58,59,75,130). HATs catalyze the addition of acetyl groups to specific lysine residues of histone proteins, whereas HDACs do the opposite, catalyzing the removal of these groups.…”

Section: Histone Acetylation and Phosphorylationmentioning

confidence: 99%

Disturbed Flow-Induced Endothelial Proatherogenic Signaling Via Regulating Post-Translational Modifications and Epigenetic Events

Heo

Berk

Abe

2016

Antioxidants & Redox Signaling

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Significance: Hemodynamic shear stress, the frictional force exerted onto the vascular endothelial cell (EC) surface, influences vascular EC functions. Atherosclerotic plaque formation in the endothelium is known to be site specific: disturbed blood flow (d-flow) formed at the lesser curvature of the aortic arch and branch points promotes plaque formation, and steady laminar flow (s-flow) at the greater curvature is atheroprotective. Recent Advances: Post-translational modifications (PTMs), including phosphorylation and SUMOylation, and epigenetic events, including DNA methylation and histone modifications, provide a new perspective on the pathogenesis of atherosclerosis, elucidating how gene expression is altered by d-flow. Activation of PKCf and p90RSK, SUMOylation of ERK5 and p53, and DNA hypermethylation are uniquely induced by d-flow, but not by s-flow. Critical Issues: Extensive cross talk has been observed among the phosphorylation, SUMOylation, acetylation, and methylation PTMs, as well as among epigenetic events along the cascade of d-flow-induced signaling, from the top (mechanosensory systems) to the bottom (epigenetic events). In addition, PKCf activation plays a role in regulating SUMOylation-related enzymes of PIAS4, p90RSK activation plays a role in regulating SUMOylation-related enzymes of Sentrin/SUMO-specific protease (SENP)2, and DNA methyltransferase SUMOylation may play a role in d-flow signaling. Future Directions: Although possible contributions of DNA events such as histone modification and the epigenetic and cytosolic events of PTMs in d-flow signaling have become clearer, determining the interplay of each PTM and epigenetic event will provide a new paradigm to elucidate the difference between d-flow and s-flow and lead to novel therapeutic interventions to inhibit plaque formation. Antioxid. Redox Signal. 25,[435][436][437][438][439][440][441][442][443][444][445][446][447][448][449][450]

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Histone Deacetylase (HDAC) Inhibitors Down-Regulate Endothelial Lineage Commitment of Umbilical Cord Blood Derived Endothelial Progenitor Cells

Cited by 20 publications

References 35 publications

Flow signaling and atherosclerosis

Flow signaling and atherosclerosis

Histone deacetylase inhibitors interfere with angiogenesis by decreasing endothelial VEGFR‐2 protein half‐life in part via a VE‐cadherin‐dependent mechanism

Disturbed Flow-Induced Endothelial Proatherogenic Signaling Via Regulating Post-Translational Modifications and Epigenetic Events

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