Trends in Pharmacological Sciences
ReviewEpigenetic-related therapeutic challenges in cardiovascular disease
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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These authors contributed equally to this article.