Epigenetic Regulation of Endothelial Cell Function by Nucleic Acid Methylation in Cardiac Homeostasis and Disease

Russell‐Hallinan, Adam; Watson, Chris; O'Dwyer, Denis; Grieve, David; O’Neill, Karla

doi:10.1007/s10557-020-07019-4

Cited by 12 publications

(8 citation statements)

References 207 publications

(287 reference statements)

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“…Current advancements in epigenetic research, including epitranscriptomic regulation, suggested its role in regulating cardiovascular functions and kindled the hopes for effective RNA-based therapeutics to manage CVD ( 14 , 15 ). Recent studies have improved our understanding of N 6 -methyladenosine (m 6 A) mRNA methylation and its functional importance in RNA stability, translation efficiency, splicing, processing and degradation ( 16 – 21 ).…”

Section: Introductionmentioning

confidence: 99%

ALKBH5 Regulates SPHK1-Dependent Endothelial Cell Angiogenesis Following Ischemic Stress

Kumari

Dutta

Ranjan

et al. 2022

Front. Cardiovasc. Med.

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BackgroundEndothelial cells dysfunction has been reported in many heart diseases including acute myocardial infarction, and atherosclerosis. The molecular mechanism for endothelial dysfunction in the heart is still not clearly understood. We aimed to study the role of m6A RNA demethylase alkB homolog 5 (ALKBH5) in ECs angiogenesis during ischemic injury.Methods and ResultsECs were treated with ischemic insults (lipopolysaccharide and 1% hypoxia) to determine the role of ALKBH5 in ECs angiogenesis. siRNA mediated ALKBH5 gene silencing was used for examining the loss of function. In this study, we report that ALKBH5 levels are upregulated following ischemia and are associated with maintaining ischemia-induced ECs angiogenesis. To decipher the mechanism of action, we found that ALKBH5 is required to maintain eNOS phosphorylation and SPHK1 protein levels. ALKBH5 silencing alone or with ischemic stress significantly increased SPHK1 m6A mRNA methylation. In contrast, METTL3 (RNA methyltransferase) overexpression resulted in the reduced expression of SPHK1.ConclusionWe reported that ALKBH5 helps in the maintenance of angiogenesis in endothelial cells following acute ischemic stress via reduced SPHK1 m6A methylation and downstream eNOS-AKT signaling.

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Section: Introductionmentioning

confidence: 99%

ALKBH5 Regulates SPHK1-Dependent Endothelial Cell Angiogenesis Following Ischemic Stress

Kumari

Dutta

Ranjan

et al. 2022

Front. Cardiovasc. Med.

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“…For example, studies have linked DNA methylation with heart failure (HF) [50][51][52] . EC dysfunction is a critical mechanism in HF pathogenesis 53,54 . Current published data on DNA methylation modifications in septic patients have been predominantly examined in mixed populations of circulating cells 5,6 .…”

Section: Discussionmentioning

confidence: 99%

Shock drives a highly coordinated transcriptional and DNA methylation response in the endothelium

Ramos

Martino

Chuy

et al. 2022

Preprint

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Interleukin 6 (IL-6) is a major mediator of the cytokine storm during shock. Its actions on the endothelium lead to pathological vascular leakage, leukocyte adhesion, and coagulopathy, which may result in multiorgan dysfunction and potentially death. Many shock survivors suffer long-term sequelae. We hypothesize that shock-induced endothelial epigenetic changes are involved in orchestrating these chronic pathological changes. Here, we interrogated the DNA methylation changes in the kidney endothelium after a challenge with lipopolysaccharides (LPS) in wilt type (WT) mice and in mice lacking endothelial SOCS3 (SOCS3iEKO). We identified 2596 differentially methylated positions (DMP) after an LPS challenge in WT mice. Notably, lack of endothelial SOCS3 leads to a highly divergent response, with 3564 DMP in response to LPS in SOCS3iEKO vs WT mice. Consistent with the hyper-inflammatory response in SOCS3iEKO mice, gene ontology analysis shows an enrichment in genes associated with an inflammatory response. To assess whether endothelial cells respond to IL-6 signaling directly by inducing DNA methylation changes, we challenged human umbilical vein endothelial cells in culture with IL-6 for 72 hours prior to methylomics assays. DNA methylation modifications were observed in sites associated with pathways regulating the regulation of cell adhesion, proliferation, and cytokine signaling. To determine the stability of these changes, we treated cells with IL-6 for 72h, followed by 96h in the absence of IL-6. We found that 40% of the DMP remained modified after the cytokine wash with a mean difference of less than 2% when comparing washed (72+96h) vs. non-washed cells (72h alone), suggesting that many changes in the endothelial methylome may remain in place for prolonged periods. In summary, persistent activation of endothelial IL-6 signaling leads to endothelial DNA methylation changes. Together, our data demonstrate that in response to pro-inflammatory stimuli, the endothelium elicits epigenetic changes that are at least in part due to IL-6/STAT3/SOCS3 signaling. These changes may regulate pathways associated with reduced long-term survival and chronic organ damage after shock.

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“…In this process, the overexpression of m6A RNA methylase METTL3 plays an important role in increasing the levels of mitogen activated protein (MAP) 3K6, MAP4K5 and MAPK14, which leads to cardiomyocyte hypertrophy (62,63). In vitro experiments confirmed that inhibition of METTL3 could effectively block cardiomyocyte hypertrophy (73)(74)(75). Nearly a quarter of transcripts in human heart are related to m6A methylation, and FTO gene knockout can lead to impaired cardiac function (76).…”

Section: M6a Methylation and Calcium Homeostasismentioning

confidence: 99%

“…Endothelial cells are the main cell type involved in coordinating the pathological changes of heart failure, and their surface is often the direct place of a variety of inflammatory reactions (75). During the occurrence and development of heart failure, chronic inflammatory reaction can continuously promote the abnormal changes of myocardial structure and function (71,77).…”

Section: M6a Methylation and Inflammatory Responsementioning

confidence: 99%

Role of m6A Methylation in the Occurrence and Development of Heart Failure

Fan

2022

Front. Cardiovasc. Med.

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N6-methyladenosine (m6A) RNA methylation is one of the most common epigenetic modifications in RNA nucleotides. It is known that m6A methylation is involved in regulation, including gene expression, homeostasis, mRNA stability and other biological processes, affecting metabolism and a variety of biochemical regulation processes, and affecting the occurrence and development of a variety of diseases. Cardiovascular disease has high morbidity, disability rate and mortality in the world, of which heart failure is the final stage. Deeper understanding of the potential molecular mechanism of heart failure and exploring more effective treatment strategies will bring good news to the sick population. At present, m6A methylation is the latest research direction, which reveals some potential links between epigenetics and pathogenesis of heart failure. And m6A methylation will bring new directions and ideas for the prevention, diagnosis and treatment of heart failure. The purpose of this paper is to review the physiological and pathological mechanisms of m6A methylation that may be involved in cardiac remodeling in heart failure, so as to explain the possible role of m6A methylation in the occurrence and development of heart failure. And we hope to help m6A methylation obtain more in-depth research in the occurrence and development of heart failure.

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Epigenetic Regulation of Endothelial Cell Function by Nucleic Acid Methylation in Cardiac Homeostasis and Disease

Cited by 12 publications

References 207 publications

ALKBH5 Regulates SPHK1-Dependent Endothelial Cell Angiogenesis Following Ischemic Stress

ALKBH5 Regulates SPHK1-Dependent Endothelial Cell Angiogenesis Following Ischemic Stress

Shock drives a highly coordinated transcriptional and DNA methylation response in the endothelium

Role of m6A Methylation in the Occurrence and Development of Heart Failure

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