Epigenetics of Atherosclerosis: Emerging Mechanisms and Methods

Khyzha, Nadiya; Alizada, Azad; Wilson, Michael D.; Fish, Jason E.

doi:10.1016/j.molmed.2017.02.004

Cited by 154 publications

(115 citation statements)

References 134 publications

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“…51 Preclinical atherosclerosis models have suggested that drugs modulating histone acetylation may be utilized to treat cardiovascular disease in the future. 52 It is noteworthy that, to date, there are some debates on the effects of HDAC inhibitors in treating experimental atherosclerosis. 50 Moreover, the side effects of HDAC inhibitor on the vascular system need to be systematically and closely monitored.…”

Section: Discussionmentioning

confidence: 99%

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Yang

Liu

et al. 2017

JAHA

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BackgroundKruppel‐like factor 2 (KLF2) is an important zinc‐finger transcription factor that maintains endothelial homeostasis by its anti‐inflammatory, ‐thrombotic, ‐oxidative, and ‐proliferative effects in endothelial cells. In light of the potent vasoprotective effects of KLF2, modulating KLF2 expression or function could give rise to new therapeutic strategies to treat cardiovascular diseases.Methods and ResultsHigh‐throughput drug screening based on KLF2 promoter luciferase reporter assay was performed to screen KLF2 activators. Real‐time PCR and western blot were used to detect gene and protein expression. Identified KLF2 activator was orally administered to ApoE−/− mice to evaluate anti‐atherosclerotic efficacy. By screening 2400 compounds in the Spectrum library, we identified suberanilohydroxamic (SAHA) acid, also known as vorinostat as a pharmacological KLF2 activator through myocyte enhancer factor 2. We found that SAHA exhibited anti‐inflammatory effects and attenuated monocyte adhesion to endothelial cells inflamed with tumor necrosis factor alpha. We further showed that the inhibitory effect of SAHA on endothelial inflammation and ensuing monocyte adhesion was KLF2 dependent using KLF2‐deficient mouse lung endothelial cells or KLF2 small interfering RNA– depleted human endothelial cells. Importantly, we observed that oral administration of SAHA reduced diet‐induced atherosclerotic lesion development in ApoE−/− mice without significant effect on serum lipid levels.ConclusionsThese results demonstrate that SAHA has KLF2‐dependent anti‐inflammatory effects in endothelial cells and provide the proof of concept that KLF2 activation could be a promising therapeutic strategy for treating atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Yang

Liu

et al. 2017

JAHA

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“…Although comprehensive data on lncRNAs remain to be collected, there is growing evidence that lncRNAs play a role in epigenetic and/or transcriptional processes through recruiting chromatin modifying and transcriptional factors to DNA among other mechanisms [61]. It was also shown that lncRNAs can participate in post-transcriptional regulators by controlling translation, splicing, and mRNA stability [62].…”

Section: Long Non-coding Rnasmentioning

confidence: 99%

In Search for Genes Related to Atherosclerosis and Dyslipidemia Using Animal Models

Poznyak

Grechko

Wetzker

et al. 2020

IJMS

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Atherosclerosis is a multifactorial chronic disease that affects large arteries and may lead to fatal consequences. According to current understanding, inflammation and lipid accumulation are the two key mechanisms of atherosclerosis development. Animal models based on genetically modified mice have been developed to investigate these aspects. One such model is low-density lipoprotein (LDL) receptor knockout (KO) mice (ldlr −/− ), which are characterized by a moderate increase of plasma LDL cholesterol levels. Another widely used genetically modified mouse strain is apolipoprotein-E KO mice (apoE −/− ) that lacks the primary lipoprotein required for the uptake of lipoproteins through the hepatic receptors, leading to even greater plasma cholesterol increase than in ldlr −/− mice. These and other animal models allowed for conducting genetic studies, such as genome-wide association studies, microarrays, and genotyping methods, which helped identifying more than 100 mutations that contribute to atherosclerosis development. However, translation of the results obtained in animal models for human situations was slow and challenging. At the same time, genetic studies conducted in humans were limited by low sample sizes and high heterogeneity in predictive subclinical phenotypes. In this review, we summarize the current knowledge on the use of KO mice for identification of genes implicated in atherosclerosis and provide a list of genes involved in atherosclerosis-associated inflammatory pathways and their brief characteristics. Moreover, we discuss the approaches for candidate gene search in animals and humans and discuss the progress made in the field of epigenetic studies that appear to be promising for identification of novel biomarkers and therapeutic targets.challenge is the lack of effective treatment approaches, which is the consequence of our incomplete understanding of the processes that underlie the pathogenesis. Genetic base is one of the most important features that are involved in the disease development.Currently, the most widely used anti-atherosclerosis drugs are statins [3]. The aim of statin therapy is reducing the blood level of low-density lipoprotein (LDL) cholesterol, which is a well-known pro-atherogenic agent. It was demonstrated that statin therapy reduces the risk of cardiovascular events by approximately one third [4]. However, statin therapy alone cannot be regarded as effective treatment of atherosclerosis. Increasing the plasma levels of high-density lipoprotein (HDL), which has anti-atherogenic properties, is another promising approach. Accumulating evidence shows that high levels of HDL cholesterol can inhibit atherosclerosis progression. To date, several therapeutic agents that increase HDL levels are known, including niacin, fibrates, and statins. Among the recently developed medications are apoA-I-phospholipid complexes, human apoA-I and apoA-I-mimetic peptides, and inhibitors of cholesterol ester transfer protein, which have reached the level of clinical trials. However, the inhibitor ...

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“…Despite the importance of epigenetics to cell differentiation, there have been only a small number of reports about atherosclerosis-related epigenetic changes, and some of these studies focused on endothelial cells or non-aorta atherosclerosis [5]. A comparison of atherosclerotic human femoral artery samples with mammary artery samples as controls indicated disease-related DNA hypomethylation of gene and promoter regions [6]; however, non-disease related tissue-specific differences might be major contributors to the observed differential methylation.…”

Section: Introductionmentioning

confidence: 99%

Atherosclerosis-associated differentially methylated regions can reflect the disease phenotype and are often at enhancers

et al. 2019

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Background and aims: Atherosclerosis is a widespread and complicated disease involving phenotypic modulation and transdifferentiation of vascular smooth muscle cells (SMCs), the predominant cells in aorta, as well as changes in endothelial cells and infiltrating monocytes. Alterations in DNA methylation are likely to play central roles in these phenotypic changes, just as they do in normal differentiation and cancer. Methods: We examined genome-wide DNA methylation changes in atherosclerotic aorta using more stringent criteria for differentially methylated regions (DMRs) than in previous studies and compared these DMRs to tissue-specific epigenetic features. Results: We found that disease-linked hypermethylated DMRs account for 85% of the total atherosclerosis-associated DMRs and often overlap aorta-associated enhancer chromatin. These hypermethylated DMRs were associated with functionally different sets of genes than were atherosclerosis-linked hypomethylated DMRs. The extent and nature of the DMRs could not be explained as direct effects of monocyte/macrophage infiltration. Among the known atherosclerosis- and contractile SMC-related genes that exhibited hypermethylated DMRs at aorta enhancer chromatin were ACTA2 (aorta α2 smooth muscle actin), ELN (elastin), MYOCD (myocardin), C9orf3 (miR-23b and miR-27b host gene), and MYH11 (smooth muscle myosin). Our analyses also suggest a role in atherosclerosis for developmental transcription factor genes having little or no previous association with atherosclerosis, such as, NR2F2 (COUP-TFII) and TBX18. Conclusions: We provide evidence for atherosclerosis-linked DNA methylation changes in aorta SMCs that might help minimize or reverse the standard contractile character of many of these cells by down-modulating aorta SMC-related enhancers, thereby facilitating pro-atherosclerotic phenotypic changes in many SMCs.

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Epigenetics of Atherosclerosis: Emerging Mechanisms and Methods

Cited by 154 publications

References 134 publications

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

In Search for Genes Related to Atherosclerosis and Dyslipidemia Using Animal Models

Atherosclerosis-associated differentially methylated regions can reflect the disease phenotype and are often at enhancers

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