Review
Epigenetic-related therapeutic challenges in cardiovascular disease

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Highlights

  • Epigenetic-based compounds are involved in CVD prevention and therapy.

  • Some dietary compounds can modulate DNA methylation status.

  • Statins show an epigenetic control in CVD prevention through histone modifications.

Progress in human genetic and genomic research has led to the identification of genetic variants associated with specific cardiovascular diseases (CVDs), but the pathogenic mechanisms remain unclear. Recent studies have analyzed the involvement of epigenetic mechanisms such as DNA methylation and histone modifications in the development and progression of CVD. Preliminary work has investigated the correlations between DNA methylation, histone modifications, and RNA-based mechanisms with CVDs including atherosclerosis, heart failure (HF), myocardial infarction (MI), and cardiac hypertrophy. Remarkably, both in utero programming and postnatal hypercholesterolemia may affect the epigenetic signature in the human cardiovascular system, thereby providing novel early epigenetic-related pharmacological insights. Interestingly, some dietary compounds, including polyphenols, cocoa, and folic acid, can modulate DNA methylation status, whereas statins may promote epigenetic-based control in CVD prevention through histone modifications. We review recent findings on the epigenetic control of cardiovascular system and new challenges for therapeutic strategies in CVDs.

Section snippets

Epigenetics and CVD

Epigenetics refers to heritable changes in gene expression that do not require changes in the DNA sequence and which are instead mediated by chromatin-based mechanisms 1, 2. Epigenetic control is one of the main regulatory systems contributing to phenotypic differences between cell types in multicellular organisms. Epigenetic changes may explain why subjects with similar genetic backgrounds and risk factors for particular diseases can differ greatly in clinical manifestation and therapeutic

DNA methylation as a therapeutic target in CVDs

DNA methylation plays a key role in embryonic development, cell type lineage specification, X-chromosome inactivation, and genomic imprinting 2, 9. It is typically associated with low levels of gene transcription. Deregulation of DNA methylation has been linked to CVD. Methylation is carried out by DNA methyltransferases (DNMTs) which catalyze methyl group addition to the C5 position of cytosine residues (5mC) [13] (Figure 1). Several studies have found associations between DNA methylation and

In vitro studies

Little is known about the methylation of genes involved in the atherosclerotic process. Certainly, some atheroprotective genes, such as those encoding estrogen receptors ERα and ERβ (ESR1 and ESR2, respectively), are consistently hypermethylated in human coronary atherosclerotic tissues and plaque regions of ascending aorta. ERs are present in the coronary arterial wall on both smooth muscle cells (SMCs) and endothelial cells (ECs), and may protect against atherosclerosis, especially in CHD.

Histone modifications as therapeutic target in CVDs

Epigenetic alterations occur in the histone code that can modulate histone–DNA interactions and significantly influence chromatin structure, thereby modifying the accessibility of transcriptional regulators to DNA-binding elements 2, 6. The most common modifications are lysine acetylation and methylation, arginine methylation, and serine phosphorylation. Histone acetylation is catalyzed by histone acetyltransferases (HATs), and histone deacetylation is carried out by histone deacetylases

In vitro studies/animal models

The best-characterized endothelial gene implicated in cardiovascular physiology that is regulated by the histone code is NOS3. This gene codes for endothelial nitric oxide (NO) synthase, eNOS, a protein that catalyzes the formation of NO from L-arginine in blood vessels [41]. NO is a vasodilator factor that regulates vascular tone and protects against atherosclerosis development. Several NO donors and modulators of the bioactivity of NO are used in the clinic [42]. eNOS is abundantly expressed

In vitro studies/animal models and human studies

The p300 HAT inhibitor curcumin (diferuloylmethane) is a polyphenol present in a curry spice that has a diverse range of molecular targets including transcription factors, growth factors and their receptors, cytokines, enzymes, and genes regulating cell proliferation and apoptosis. Cardiovascular protective effects of this compound have been demonstrated [50]. Indeed, administration of curcumin caused significantly lowered LDL levels and increased high-density lipoprotein (HDL) levels in

RNA-based mechanisms involved in CVDs

RNA-based mechanisms constitute another method of epigenetic control. Genome sequencing and genome-wide association studies (GWAS) indicate that only a fraction of CVD risk-associated genetic variations are localized in protein-coding genes, and instead the majority are located in genomic regions that could express noncoding RNAs. RNA-based mechanisms can take place through two classes of noncoding RNAs: miRNA and long non-coding RNAs (lncRNAs) [57] (Figure 1).

miRNAs

miRNAs emerged on the scene of epigenetics as important players able to modulate gene expression by downregulating the translation of target mRNAs via inhibition of post-transcriptional events, transcript degradation, or direct translational suppression. In mammals, more than 1000 different miRNAs have been described, including miR-17, miR-92a, and miR-126 that are expressed in ECs, miR-145 expressed in SMCs, and miR-133 and miR-208a that are both expressed in cardiac muscle. Interestingly,

miRNAs in atherosclerosis

Many miRNAs have been implicated in the development of atherosclerosis. Unfortunately, the targets for most of these miRNAs have yet to be identified [62]. An example is miR-33, an intronic miRNA that is widely expressed in different cell types and tissues [63]. It was first detected within the gene encoding the sterol regulatory element-binding protein 2 (SRBP-2), a transcriptional regulator of cholesterol synthesis, which modulates the expression of genes involved in cholesterol metabolism,

miRNAs in HF

Several studies have demonstrated a significant role of miRNAs in the pathogenesis of HF. The expression of many miRNAs is altered in animal models of HF and in human cardiac patients [61]. In particular, transgenic miR-195 mice were found to develop dilated cardiomyopathy; moreover, overexpression of miR-23a, miR-23b, miR-24, miR-195, or miR-214 was found to induce hypertrophy in human cardiomyocytes [61]. Interestingly, overexpression of miR-1 and miR-133, which are downregulated in

lncRNAs

Current research also focuses on lncRNAs, a novel class of non-coding transcripts greater than 200 nt in length that play an important role in epigenetic regulation. They comprise different classes of RNA transcripts that are localized to the nucleus and are expressed at lower levels than protein-coding genes. lncRNAs participate in multiple networks of gene expression and function by influencing the formation of nuclear domains and can modulate the transcriptional status of an entire

Concluding remarks

The main fundamental steps governing epigenetic mechanisms have now been identified, and the reversible nature of epigenetic alterations has encouraged the development of therapeutic strategies targeting various epigenetic components including DNA methylation, histone modifications, and miRNAs. Indeed, several DNMT and HDAC inhibitors have been studied in clinical trials; some are now FDA approved for the treatment of other diseases such as cancer, and, more recently, histone methylation and

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