Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis

Dunn, James M.; Qiu, Haiwei; Kim, Soyeon; Jjingo, Daudi; Hoffman, Ryan; Kim, Chan Woo; Jang, In-Hwan; Son, Dong Ju; Kim, Daniel; Pan, Chenyi; Fan, Yuhong; Jordan, I. King; Jo, Hanjoong

doi:10.1172/jci74792

Cited by 249 publications

(233 citation statements)

References 76 publications

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“…We observed no changes in monocyte adhesion or pericollateral macrophage accumulation in reversed flow conditions, indicating an anti‐inflammatory role for DNMT1 that is dependent on hemodynamic context. In contrast, DNMT1 has been shown to promote EC inflammation in HUVECs exposed to atheroprone flow conditions, as demonstrated by a DNMT1‐dependent increase in monocyte adhesion 17. However, our proarteriogenic flow conditions, which include a laminar flow preconditioning phase, are different from the oscillatory, atheroprone conditions of previous studies,17 further supporting the idea that DNMT1's role in endothelial inflammation is dependent on hemodynamic context.…”

Section: Discussionsupporting

confidence: 77%

“…In contrast, DNMT1 has been shown to promote EC inflammation in HUVECs exposed to atheroprone flow conditions, as demonstrated by a DNMT1‐dependent increase in monocyte adhesion 17. However, our proarteriogenic flow conditions, which include a laminar flow preconditioning phase, are different from the oscillatory, atheroprone conditions of previous studies,17 further supporting the idea that DNMT1's role in endothelial inflammation is dependent on hemodynamic context. Furthermore, exposure to atheroprone conditions led to a chronic increase in DNMT1 expression,17 whereas our results suggest a transient increase in DNMT1 expression.…”

Section: Discussionsupporting

confidence: 77%

“…However, our proarteriogenic flow conditions, which include a laminar flow preconditioning phase, are different from the oscillatory, atheroprone conditions of previous studies,17 further supporting the idea that DNMT1's role in endothelial inflammation is dependent on hemodynamic context. Furthermore, exposure to atheroprone conditions led to a chronic increase in DNMT1 expression,17 whereas our results suggest a transient increase in DNMT1 expression. This adaptive, instead of chronic, response may contribute to a context‐dependent role of DNMT1 on monocyte adhesion to ECs.…”

Section: Discussionsupporting

confidence: 75%

“…HUVECs are both phenotypically consistent and one of the most extensively used cell culture models for study of flow‐mediated EC signaling, including numerous studies of flow responses of the arterial system17, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 (eg, atheroprone versus atheroprotective waveforms) and DNMT1‐dependent DNA methylation 17, 18. For each set of experimental comparisons, cells were used from the same cell line between subculture passages 2 to 3.…”

Section: Methodsmentioning

confidence: 99%

“…DNA methylation occurs through the activity of DNA methyltransferases (DNMTs), particularly DNMT1 postdevelopment 13, 14, 15. Recently, DNA methylation has been shown to differentially regulate flow‐mediated endothelial gene expression through DNMT1,16, 17, 18, 19 although the role of DNA methylation in the regulation of arteriogenesis has not been explored. Here, using our previous observations of differential arteriogenic capacity within collateral artery segments in vivo as a basis, we tested the central hypothesis that an augmented shear stress set point constrains arteriogenic capacity via DNMT1‐dependent endothelial cell (EC) DNA hypermethylation.…”

Section: Introductionmentioning

confidence: 99%

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DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

Heuslein

Gorick

Song

et al. 2017

JAHA

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BackgroundArteriogenesis is initiated by increased shear stress and is thought to continue until shear stress is returned to its original “set point.” However, the molecular mechanism(s) through which shear stress set point is established by endothelial cells (ECs) are largely unstudied. Here, we tested the hypothesis that DNA methyltransferase 1 (DNMT1)–dependent EC DNA methylation affects arteriogenic capacity via adjustments to shear stress set point.Methods and ResultsIn femoral artery ligation–operated C57BL/6 mice, collateral artery segments exposed to increased shear stress without a change in flow direction (ie, nonreversed flow) exhibited global DNA hypermethylation (increased 5‐methylcytosine staining intensity) and constrained arteriogenesis (30% less diameter growth) when compared with segments exposed to both an increase in shear stress and reversed‐flow direction. In vitro, ECs exposed to a flow waveform biomimetic of nonreversed collateral segments in vivo exhibited a 40% increase in DNMT1 expression, genome‐wide hypermethylation of gene promoters, and a DNMT1‐dependent 60% reduction in proarteriogenic monocyte adhesion compared with ECs exposed to a biomimetic reversed‐flow waveform. These results led us to test whether DNMT1 regulates arteriogenic capacity in vivo. In femoral artery ligation–operated mice, DNMT1 inhibition rescued arteriogenic capacity and returned shear stress back to its original set point in nonreversed collateral segments.ConclusionsIncreased shear stress without a change in flow direction initiates arteriogenic growth; however, it also elicits DNMT1‐dependent EC DNA hypermethylation. In turn, this diminishes mechanosensing, augments shear stress set point, and constrains the ultimate arteriogenic capacity of the vessel. This epigenetic effect could impact both endogenous collateralization and treatment of arterial occlusive diseases.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

Heuslein

Gorick

Song

et al. 2017

JAHA

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Epigenetic Network in Immunometabolic Disease

Geiger,

Gorica,

Mohammed

et al. 2023

Advanced Biology

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Although a large amount of data consistently shows that genes affect immunometabolic characteristics and outcomes, epigenetic mechanisms are also heavily implicated. Epigenetic changes, including DNA methylation, histone modification, and noncoding RNA, determine gene activity by altering the accessibility of chromatin to transcription factors. Various factors influence these alterations, including genetics, lifestyle, and environmental cues. Moreover, acquired epigenetic signals can be transmitted across generations, thus contributing to early disease traits in the offspring. A closer investigation is critical in this aspect as it can help to understand the underlying molecular mechanisms further and gain insights into potential therapeutic targets for preventing and treating diseases arising from immuno‐metabolic dysregulation. In this review, the role of chromatin alterations in the transcriptional modulation of genes involved in insulin resistance, systemic inflammation, macrophage polarization, endothelial dysfunction, metabolic cardiomyopathy, and nonalcoholic fatty liver disease (NAFLD), is discussed. An overview of emerging chromatin‐modifying drugs and the importance of the individual epigenetic profile for personalized therapeutic approaches in patients with immuno‐metabolic disorders is also presented.

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Delivery of Anti‐microRNA‐712 to Inflamed Endothelial Cells Using Poly(β‐amino ester) Nanoparticles Conjugated with VCAM‐1 Targeting Peptide

Dosta

Tamargo

Ramos

et al. 2021

Adv Healthcare Materials

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Endothelial cells (ECs) are an important target for therapy in a wide range of diseases, most notably atherosclerosis. Developing efficient nanoparticle (NP) systems that deliver RNA interference (RNAi) drugs specifically to dysfunctional ECs in vivo to modulate their gene expression remains a challenge. To date, several lipid‐based NPs are developed and shown to deliver RNAi to ECs, but few of them are optimized to specifically target dysfunctional endothelium. Here, a novel, targeted poly(β‐amino ester) (pBAE) NP is demonstrated. This pBAE NP is conjugated with VHPK peptides that target vascular cell adhesion molecule 1 protein, overexpressed on inflamed EC membranes. To test this approach, the novel NPs are used to deliver anti‐microRNA‐712 (anti‐miR‐712) specifically to inflamed ECs both in vitro and in vivo, reducing the high expression of pro‐atherogenic miR‐712. A single administration of anti‐miR‐712 using the VHPK‐conjugated‐pBAE NPs in mice significantly reduce miR‐712 expression, while preventing the loss of its target gene, tissue inhibitor of metalloproteinase 3 (TIMP3) in inflamed endothelium. miR‐712 and TIMP3 expression are unchanged in non‐inflamed endothelium. This novel, targeted‐delivery platform may be used to deliver RNA therapeutics specifically to dysfunctional endothelium for the treatment of vascular disease.

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Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis

Cited by 249 publications

References 76 publications

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

Epigenetic Network in Immunometabolic Disease

Delivery of Anti‐microRNA‐712 to Inflamed Endothelial Cells Using Poly(β‐amino ester) Nanoparticles Conjugated with VCAM‐1 Targeting Peptide

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