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EPIGENETICS IN DIABETES AND CARDIOVASCULAR RISK

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Epigenetic mechanisms

Epigenome comprises all hereditable changes without gene alterations to respond to external/internal stimuli in different diseases (Dirks 2016). The most frequent epigenetic modifications are DNA methylation, histone modifications, and RNA based alterations that involve microRNAs (miRNAs) and long noncoding RNAs (LncRNAs). DNA methylation involving regulatory genes of innate and adaptive immune response remained the principal hallmark of diabetes (Sommese 2017, Zullo 2017, Picascia 2015a). In addition, recent data have emphasized that diet, infections, and intestinal microbiota would interact with genetic risk for β-cell-related autoimmunity altering the epigenetic profile at pancreatic level (Jerram 2018).

Epigenetic tags in primary and secondary prevention of diabetes and cardiovascular disease

In Table 1 we report the current status of the main published epigenetic mechanisms involved in primary and secondary prevention of diabetes and cardiovascular disease.

Primary prevention

An aberrant activity of O-GlcNAc transferase (OGT) plays a relevant role in cardiovascular complications associated with T2D by increasing oxidative stress in endothelial cells A recent in vitro study has reported that human aortic endothelial cells (HAECs) exposed to high glucose induced a simultaneous OGT over-expression and miR-200a and miR-200b down-regulation, which led to inflammation (Lo 2018). By transfection assays with miR-200a and miR-200b mimics, a significant decrease in OGT expression level was reported counteracting inflammatory process in HAECs. Thus, administration of miR-200a and miR-200b might assume a crucial role in primary prevention and management of vascular complications in diabetic patients (Lo 2018).

Human aortic valvular endothelial cells (HAVECs) in vitro were transfected with miR-18a-5p mimic, induced the switch of endothelial cells toward endothelial-mesenchymal phenotype contributing to cardiac fibrosis (Geng 2017). In particular, high glucose treatment showed a down-regulation of miR-18-5p associated with an over-expression of Notch2 signal contributing to fibroblast-like phenotype (Geng 2017). Then, the miR-18-5p/Notch2 pathway might act as innovative target to counteract myocardial fibrosis in diabetic cardiomyopathy (Geng 2017).

Hyperglycemia can alter the vital plasticity of smooth muscle cells (SMCs) during vascular development, repair and adaptation contributing to progression of atherosclerosis and bypass graft failure. A persistent over-expression of miR-143 and miR-145 was observed in SMCs from explants of saphenous veins (SV) obtained from patients with T2D ex vivo leading to an impaired cell morphology and function (Riches 2014). These results indicated that a down-regulation of these miRNAs in SV-SMCs might contribute to restore vascular function in T2D patients preventing the cardiovascular dysfunctions (Riches K, 2014).

The prospective Bruneck Study conducted on Caucasian population reported that higher levels of liver circulating miR-122 was related to dysmetabolic features such as an adverse lipid profile, insulin resistance, obesity, metabolic syndrome, and T2D. However, no correlation with cardiovascular events was observed and it remains to be clarified if these findings are equally applicable to other ethnicities (Willeit 2017).

Secondary prevention

A long non-coding RNA (Lnc-DC) sited on chromosome 17 near STAT3 gene can directly bind the transcription factor STAT3 playing a relevant role in pro-inflammatory cytokine expression in peripheral blood mononuclear cells (PBMCs) associated with atherosclerotic plaque formation (Alikhah 2018). To examine the role of these lnc-DC in diabetic cardiovascular diseases (CHD), a recent case-control study ex vivo was performed using blood samples from 36 CHD- patients, 18 with diabetes mellitus (DM+) and 18 without diabetes mellitus (DM-), plus 37 CHD+ patients, 24 DM+ and 13 DM- referred to Tehran Heart Center outpatient clinic for coronary angiography (Alikhah 2018). Although the expression level of lnc-DC did not show significance level in DM patients, the overexpression of lnc-DC in CHD+/DM+ vs CHD-/DM- patients suggested that lncRNA might play a role in the pathogenesis of diabetes-related CHD (Alikhah 2018).

During inflammation platelet-derived growth factor (PDGF) and tumor necrosis factor-alpha (TNF-α) induced activation of vascular SMCs and ECs causing lower level of let-7 miRNA via Lin28b, a negative regulator of let-7 biogenesis (Brennan 2017). Interestingly, the administration of let-7 mimic to human carotid plaque ex vivo showed a significant modulation of pro-inflammatory cytokines. Then, restoration of let-7 expression could provide a novel therapeutic strategy for an anti-inflammatory approach in diabetic vascular disorder (Brennan 2017).

A case-control study ex vivo performed on the left ventricular of diabetic and non-diabetic HF patients (LV apex tissue from patients) undergoing left ventricular assist device implantation reported that diabetes exacerbated cardiac autophagy and hypertrophy by down-regulation of miR-133a suggesting a cardioprotective role in diabetic hearts (Nandi 2015).

A study ex vivo and in vitro showed that circulating miR-34a from early stages in asymptomatic T2D subjects, human adult cardiomyocytes cultured with high glucose and cardiac progenitor cells (CPCs) isolated from diabetic heart showed a significant up-regulation of miR-34a and down-regulation of SIRT1, associated with a great increase in pro-apoptotic caspase-3/7 activity (Fomison-Nurse 2018). Moreover, the overexpression of miR-34a was also correlated with HbA1c level. Knockdown of miR-34a restored the expression of SIRT1 in both cardiomyocytes and CPCs suggesting that miR-34a is able to mediate pathological changes early in the diabetic heart. Besides, miR-34a might be a novel diagnostic tool for determining the senescence of heart (Fomison-Nurse 2018).

A case-control study was performed with blood samples from subjects grouped in CHD patients, patients with T2D and CHD, and control subjects to examine the role of miR-24 and its target YKL-40, an inflammatory glycoprotein involved in endothelial dysfunction (Deng 2017). Levels of circulating miR-24 were lower in peripheral blood of T2D/CHD and CHD patients than controls. Besides, miR-24 was strongly associated with T2D/CHD and negatively correlated with YKL-40 in T2D/CHD and T2D patients. Then, it was suggested that circulating miR-24 might be a predictive biomarker of T2D and CHD (Deng 2017).

A down-regulation in vitro of miRNA-9 in cardiomyocytes exposed to high glucose treated and in human diabetic hearts was observed and strongly correlated with higher levels of ELAVL1, a pro-inflammatory molecule that played a critical role in the progression of heart failure (HF) via activation of caspase-1 (Jeyabal 2016). Administration of miR-9 mimics attenuated hyperglycemia-induced ELAVL1 and inhibited cardiomyocyte apotosis highlighting the potential therapeutic role of targeting miR-9/ELAVL1 pathway in preventing cardiomyocyte injury during HF in diabetics (Jeyabal 2016).

Only miRNAs in primary and in secondary prevention were found.

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