Angioplasty-induced epigenomic remodeling entails BRD4 and EZH2 hierarchical regulations

AbstractAtherosclerosis is commonly treated with angioplasty which, however, evokes neointimal hyperplasia (IH) and recurrent stenotic diseases. Epigenomic investigation was lacking on post-angioplasty IH. The histone acetylation reader BRD4 and H3K27me3 writer EZH2 are potent epigenetic factors; their relationship is little understood. Through genome-wide survey in the rat angioplasty model, we studied BRD4 and EZH2 functional regulations involved in IH.We performed chromatin immunoprecipitation sequencing (ChIPseq) using rat carotid arteries. While H3K27me3 ChIPseq signal prevalently intensified in balloon-injured (vs uninjured) arteries, BRD4 and H3K27ac became more enriched at Ezh2. Indeed, BRD4-siRNA or CRISPR-deletion of BRD4-associated enhancer abated the smooth muscle cell (SMC) expression of EZH2, and SMC-specific BRD4 knockout in BRD4fl/fl; Myh11CreERT2 mice reduced both H3K27me3 and IH in wire-injured femoral arteries. In accordance, post-angioplasty IH was exacerbated and mitigated, respectively, by lentiviral expression and pharmacological inhibition of EZH2/1; EZH2 (or EZH1) loss- and gain-of-function respectively attenuated and aggravated pro-IH SMC proliferative behaviors. Furthermore, while H3K27me3 ChIPseq signal magnified at P57 and ebbed at Ccnd1 and Uhrf1 after injury, silencing either EZH2 or EZH1 in SMCs up-regulated P57 and down-regulated Ccnd1 and Uhrf1.In summary, our results reveal an upsurge of EZH2/H3K27me3 after angioplasty, BRD4’s control over EZH2 expression, and non-redundant EZH2/1 functions. As such, this study unravels angioplasty-induced loci-specific H3K27me3/ac redistribution in the epigenomic landscape rationalizing BRD4/EZH2-governed pro-IH regulations.

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Niclosamide inhibits vascular smooth muscle cell proliferation and migration and attenuates neointimal hyperplasia in injured rat carotid arteries

British Journal of Pharmacology ◽

10.1111/bph.14182 ◽

2018 ◽

Vol 175 (10) ◽

pp. 1707-1718 ◽

Cited By ~ 6

Author(s):

Xiao-Lin Xiao ◽

Nan Hu ◽

Xin-Zi Zhang ◽

Man Jiang ◽

Chang Chen ◽

...

Keyword(s):

Cell Proliferation ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Carotid Arteries ◽

Neointimal Hyperplasia ◽

Cell Proliferation And Migration ◽

And Migration ◽

Proliferation And Migration

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In Silico Prediction of the Mechanobiological Response of Arterial Tissue: Application to Angioplasty and Stenting

Journal of Biomechanical Engineering ◽

10.1115/1.4004492 ◽

2011 ◽

Vol 133 (8) ◽

Cited By ~ 23

Author(s):

Colin J. Boyle ◽

Alexander B. Lennon ◽

Patrick J. Prendergast

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Time Course ◽

Neointimal Hyperplasia ◽

Cell Activity ◽

Tissue Response ◽

Cell Phenotype ◽

Modeling Approach ◽

Arterial Tissue

One way to restore physiological blood flow to occluded arteries involves the deformation of plaque using an intravascular balloon and preventing elastic recoil using a stent. Angioplasty and stent implantation cause unphysiological loading of the arterial tissue, which may lead to tissue in-growth and reblockage; termed “restenosis.” In this paper, a computational methodology for predicting the time-course of restenosis is presented. Stress-induced damage, computed using a remaining life approach, stimulates inflammation (production of matrix degrading factors and growth stimuli). This, in turn, induces a change in smooth muscle cell phenotype from contractile (as exists in the quiescent tissue) to synthetic (as exists in the growing tissue). In this paper, smooth muscle cell activity (migration, proliferation, and differentiation) is simulated in a lattice using a stochastic approach to model individual cell activity. The inflammation equations are examined under simplified loading cases. The mechanobiological parameters of the model were estimated by calibrating the model response to the results of a balloon angioplasty study in humans. The simulation method was then used to simulate restenosis in a two dimensional model of a stented artery. Cell activity predictions were similar to those observed during neointimal hyperplasia, culminating in the growth of restenosis. Similar to experiment, the amount of neointima produced increased with the degree of expansion of the stent, and this relationship was found to be highly dependant on the prescribed inflammatory response. It was found that the duration of inflammation affected the amount of restenosis produced, and that this effect was most pronounced with large stent expansions. In conclusion, the paper shows that the arterial tissue response to mechanical stimulation can be predicted using a stochastic cell modeling approach, and that the simulation captures features of restenosis development observed with real stents. The modeling approach is proposed for application in three dimensional models of cardiovascular stenting procedures.

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