Epigenetic Regulation of Vascular Smooth Muscle Cells by Histone H3 Lysine 9 Dimethylation Attenuates Target Gene-Induction by Inflammatory Signaling

Harman, Jennifer L.; Dobnikar, Lina; Chappell, Joel; Stokell, Benjamin G.; Dalby, Amanda; Foote, Kirsty; Finigan, Alison; Freire-Pritchett, Paula; Taylor, A.; Worssam, Matthew D; Madsen, Ralitsa R.; Loche, Elena; Uryga, Anna; Bennett, Martin R.; Jørgensen, Helle F.

doi:10.1161/atvbaha.119.312765

Cited by 33 publications

(25 citation statements)

References 68 publications

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“…Except for regulating autophagy, EHMT2 was recently reported to regulating inflammatory VSMC phenotype by dimethylating H3K9 (H3K9me2). H3K9me2 was enriched at a subset of inflammation-responsive gene promoters, including MMP3, MMP9, MMP12, and IL6, in VSMCs to affect post-injury neointima formation and atherosclerotic lesions [44]. These studies indicated that EHMT2 may be involved in aortic dissection, aortic aneurysm and atherosclerosis via regulating autophagy or inflammatory response, but the exact roles and mechanisms of EHMT2 in these vasculopathy need further investigation.…”

Section: Discussionmentioning

confidence: 94%

EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation

Chen¹,

Hu²,

Huo³

et al. 2020

Int. J. Biol. Sci.

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Although EHMT2 (also known as G9a) plays a critical role in several kinds of cancers and cardiac remodeling, its function in vascular smooth muscle cells (VSMCs) remains unknown. In the present study, we revealed a novel function of EHMT2 in regulating autophagic cell death (ACD) of VSMC. Inhibition of EHMT2 by BIX01294 or knockdown of EHMT2 resulted in reduced VSMC numbers which were independent of proliferation and apoptosis. Interestingly, EHMT2 protein levels were significantly decreased in VSMCs treated with autophagic inducers. Moreover, more autophagic vacuoles and accumulated LC3II were detected in VSMCs treated with BIX01294 or lenti-shEHMT2 than their counterparts. Furthermore, we found that EHMT2 inhibited the ACD of VSMCs by suppressing autophagosome formation. Mechanistically, the pro-autophagic effect elicited by EHMT2 inhibition was associated with SQSTM1 and BECN1 overexpression. Moreover, these detrimental effects were largely nullified by SQSTM1 or BECN1 knockdown. More importantly, similar results were observed in primary human aortic VSMCs. Overall, these findings suggest that EHMT2 functions as a crucial negative regulator of ACD via decreasing SQSTM1 or BECN1 expression and that EHMT2 could be a potent therapeutic target for cardiovascular diseases (e.g., aortic dissection).

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Section: Discussionmentioning

confidence: 94%

EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation

Chen¹,

Hu²,

Huo³

et al. 2020

Int. J. Biol. Sci.

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“…Our study identifies additional phases of activation where VSMCs that could be subject to regulation, including VSMC priming, cell cycle activation, VSMC loss and migration across the intimal layer. Understanding how documented regulators of VSMC function in disease 1,36,41 and novel pathways - such as retinoic acid signaling and efferocytosis identified by scRNA-seq analysis of atherosclerotic plaque cells 16,33 -impact on these mechanisms will provide important insight into how targeting of vessel wall cells could be achieved to limit cell accumulation and disease severity. The existence of cells in human arteries that correspond to the murine SCA1+ VSMCs and the genetic evidence linking variable expression to cardiovascular disease highlight this cell population a promising starting point.…”

Section: Discussionmentioning

confidence: 99%

Primed smooth muscle cells acting as first responder cells in disease

Worssam

Lambert

et al. 2020

Preprint

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Rationale; Vascular smooth muscle cell (VSMC) dysregulation is a hallmark of vascular disease, including atherosclerosis. In particular, the majority of cells within atherosclerotic lesions are generated from pre-existing VSMCs and a clonal nature has been documented for VSMC-derived cells in multiple disease models. However, the mechanisms underlying the generation of oligoclonal lesions and the phenotype of proliferating VSMCs are unknown. Objective; To understand the cellular mechanisms underlying clonal VSMC expansion in disease. Methods and Results; Here we analyse clonal dynamics in multi-color lineage-traced animals over time after vessel injury. We demonstrate that VSMC proliferation is initiated in a small fraction of VSMCs that initially expand clonally in the medial layer and then migrate to form the oligoclonal neointima. Selective activation of VSMC proliferation also occurs in vitro, suggesting that this is a cell-autonomous feature. Mapping of VSMC trajectories using single-cell RNA-sequencing reveals a continuum of cellular states after injury and suggests that VSMC proliferation initiates in cells that have downregulated the contractile phenotype and show evidence of pronounced phenotypic switching. We show that proliferation is associated with induced expression of stem cell antigen 1 (SCA1) and the expression signature previously identified in SCA1+ VSMCs in healthy arteries. A remarkably increased proliferation of SCA1+ VSMCs, directly validated in functional assays, indicates that SCA1+ VSMCs act as "first responders" in vascular injury. Early atherosclerotic lesions also had clonal VSMC contribution and we show that the proliferation-associated injury response is conserved in plaque VSMCs, extending these findings to atherosclerosis. Finally, we identify VSMCs in healthy human arteries that correspond to the SCA1+ state in mouse VSMCs and show that genes identified as differentially expressed in this human VSMC subpopulation are enriched for genes showing genetic association with cardiovascular disease. Conclusions; We show that cell-intrinsic, selective VSMC activation drives clonal proliferation after injury and in atherosclerosis. Our study suggests that healthy mouse and human arteries contain VSMCs characterised by expression of disease-associated genes that are predisposed for proliferation. Targeting such "first responder" cells in patients undergoing vascular surgery could effectively prevent injury-associated VSMC activation and neoatherosclerosis.

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“…It has been reported that histone H3K9me2 in patients with hyperthyroidism is lower than it is in a normal control group, while the expression of the JHDM2A gene is significantly higher than it is in a normal control group (Yan et al, 2019). It has been observed that the decrease in H3K9me2 in vascular smooth muscle cells is accompanied by an increase in inflammation, and there is a high level of H3K9me2 in the promoter region of arteriosclerosis genes associated with cardiovascular disease (Harman et al, 2019). In addition, there is evidence that histone modification plays an important role in regulating the expression of DNA damage repair‐related factors (Mao & Wyrick, 2016).…”

Section: Discussionmentioning

confidence: 99%

Histone demethylase JHDM2A regulates H3K9 dimethylation in response to arsenic‐induced DNA damage and repair in normal human liver cells

Zhang

Tang

Yang

et al. 2020

J of Applied Toxicology

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Long‐term arsenic exposure is a worldwide public health problem that causes serious harm to human health. The liver is the main target organ of arsenic toxicity; arsenic induces disruption of the DNA damage repair pathway, but its mechanisms remain unclear. In recent years, studies have found that epigenetic mechanisms play an important role in arsenic‐induced lesions. In this study, we conducted experiments in vitro using normal human liver cells (L‐02) to explore the mechanism by which the histone demethylase JHDM2A regulates H3K9 dimethylation (me2) in response to arsenic‐induced DNA damage. Our results indicated that arsenic exposure upregulated the expression of JHDM2A, downregulated global H3K9me2 modification levels, increased the H3K9me2 levels at the promoters of base excision repair (BER) genes (N‐methylpurine‐DNA glycosylase [MPG], XRCC1 and poly(ADP‐ribose)polymerase 1) and inhibited their expression levels, causing DNA damage in cells. In addition, we studied the effects of overexpression and inhibition of JHDM2A and found that JHDM2A can participate in the molecular mechanism of arsenic‐induced DNA damage via the BER pathway, which may not be involved in the BER process because H3K9me2 levels at the promoter region of the BER genes were unchanged following JHDM2A interference. These results suggest a potential mechanism by which JHDM2A can regulate the MPG and XRCC1 genes in the process of responding to DNA damage induced by arsenic exposure and can participate in the process of DNA damage repair, which provides a scientific basis for understanding the epigenetic mechanisms and treatments for endemic arsenic poisoning.

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Epigenetic Regulation of Vascular Smooth Muscle Cells by Histone H3 Lysine 9 Dimethylation Attenuates Target Gene-Induction by Inflammatory Signaling

Abstract: Supplemental Digital Content is available in the text.

Cited by 33 publications

References 68 publications

EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation

EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation

Primed smooth muscle cells acting as first responder cells in disease

Histone demethylase JHDM2A regulates H3K9 dimethylation in response to arsenic‐induced DNA damage and repair in normal human liver cells

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