The vascular epigenome in patients with obesity and type 2 diabetes: opportunities for personalized therapies

Abstract

Our genetic background provides limited information on individual risk of developing vascular complications overtime. New biological layers, namely epigenetic modifications, are now emerging as potent regulators of gene expression thus leading to altered transcriptional programs and vascular disease phenotypes. Such epigenetic modifications, defined as changes to the genome that do not involve changes in DNA sequence, are generally induced by environmental factors and poor lifestyle habits. Of note, adverse epigenetic signals acquired during life can be transmitted to the offspring thus leading to premature alterations of the epigenetic and transcriptional landscape eventually leading to early endothelial dysfunction and vascular senescence. Modifications of the epigenome play a pivotal role in the pathophysiology of cardiometabolic disturbances such as obesity and type 2 diabetes. In these patients, changes of DNA methylation and chromatin structure contribute to alter pathways regulating insulin sensitivity, glucose homeostasis, adipogenesis and vascular function. In this perspective, unveiling the ‘epigenetic landscape’ in cardiometabolic patients may help to identify new players implicated in obesity and diabetes-related vascular dysfunction and may pave the way for personalized therapies in this setting. In the present review, we discuss current knowledge of the epigenetic routes implicated in vascular damage and cardiovascular disease in patients with metabolic alterations.

Proteomic and Structural Manifestations of Cardiomyopathy in Rat Models of Obesity and Weight Loss

“…Costa and Franco provided a broad view on cardiac transcriptome changes produced by obesity showing that expression of genes involved in cellular architecture and lipid metabolism was affected which supports our data ( 53 ). The regulation of gene expression may be a consequence of the plethora of epigenetic modification present in cardiometabolic diseases and epigenetic therapies may represent a new frontier in cardiovascular medicine ( 58 ).…”

Role of Epigenetics and Metabolomics in Predicting Endothelial Dysfunction in Type 2 Diabetes

“…Recent studies have demonstrated a link between histone modifications and vascular complications of diabetes [ 43 ] In particular, it has been shown a key role of epigenetic modifications in vascular inflammation [ 77,78 ]…”

“…DNA methylation is a key regulator of gene expression and one of the most well-characterized epigenetic modifications. It consists of the conversion of cytosine to 5-methylcytosine via the covalent transfer of a methyl group to the fifth carbon position of cytosine [41] It mainly occurs at promoter regions characterized by cytosines and guanines, called CpG islands [42,43] The methyl group responsible for DNA and histone methylation originates from S-adenosyl methionine [42] This epigenetic mark remains stable during cell division and regulates a wide range of cellular mechanisms including transcription and chromosomal stability, and plays a pivotal role in embryonic development, genomic imprinting, and X-chromosome inactivation [44] DNA methylation is established by DNA methyltransferases (DNMTs). DNMT1 is responsible for the maintenance of methylation, whereas DNMT3a and DNMT3b mediate de novo methylation of DNA [45] DNA methylation is a reversible modification that can be removed by the ten-eleven translocation enzymes (TETs), or by a reduced activity of DNMT1.…”

“…Methylation of histone proteins may have different effects on gene expression. For example, methylations of H3R17, H4R3, and H3K4 are linked with transcriptional activation, whereas methylations of H3K9, H3K27, and H4K20 are considered as markers of transcriptional repression [76] Recent studies have demonstrated a link between histone modifications and vascular complications of diabetes [43] In particular, it has been shown a key role of epigenetic modifications in vascular inflammation [77,78] One of the most important inflammatory pathways is NF-𝜅B signaling, able to induce the release of inflammatory factors such as cytokines. The methylation status of histones on the NF-𝜅B p65 gene appears to play a key role in the regulation of inflammatory responses under diabetic conditions.…”

An Overview of the Relationship Between Dietary Behavior and Lifestyle to Health at Molecular Biology Mechanism

“…Obesity, type 2 diabetes, and a high-fat diet are causes that increase the methylation of the FGF21 gene promoter. They inhibit the transcription process and expression of the FGF21 gene, leading to an increase in the formation and accumulation of white fat tissue, and worsening inflammation leading to pancreatic cancer and low bone joint inflammation [36,37]. Short-chain fatty acids including butyric acid and α-lipoic acid are products of the fermentation process of gut bacteria due to a fiber-rich diet.…”