Epigenetic Modifications and Non-Coding RNA in Diabetes-Mellitus-Induced Coronary Artery Disease: Pathophysiological Link and New Therapeutic Frontiers

Figure 1. Pathways leading to atherosclerosis in hyperglycemia. Intracellular and extracellular molecular mechanisms underlying hyperglycemia-induced endothelial dysfunction. ROS, Reactive oxygen species; DAG, diacylglycerol; PKC, Protein kinase C; eNOS, endothelial Nitric Oxide Synthase; NFkB, Nuclear Factor κB; ECM, extracellular matrix; PAI—1, Plasminogen activator inhibitor-1; End1, endothelin 1; VEGF, Vascular endothelial growth factor; AGE, Advanced glycation end products; and RAGE, receptor for advanced glycation end products.

Figure 2. Epigenetic modifications triggered by hyperglycemia. Hyperglycemia triggers the following epigenetic modifications: DNA methylation, histone modifications and non-coding RNA mediated control. siRNA, short interfering RNA; miRNA, micro RNA; lncRNA, long non-coding RNA; and circRNA, circular RNA.

Figure 3. Hyperglycemia and NF-kB pathway activation. Endothelial cells exposed to transient hyperglycemia are characterized by the persistence of NFκB-p65 gene (RELA) activation, induced by DNA demethylation of the NF-κB promoter at CpGs islands through TET2 upregulation. Hyperglycemia activates the NF-κB-p65 gene in endothelial cells also by mono-methylation of lysine 4 on histone 3 (H3K4m1) through histone methyltransferase Set7 and demethylation of H3K9 on the p65 promoter by lysine-specific demethylase 1. Hyperglycemia also influences the SUMOylation of I𝜅B𝛼, which is the main inhibitor of NF-κB dimers: when IκBα is SUMOylated, it is resistant to ubiquitin-induced degradation, and it inhibits NF-κB; in high glucose conditions, SUMOylation of I𝜅B𝛼 is decreased, with consequent activation of the NF-κB pathway. NF-κB upregulation leads to increasing its gene targets, causing vascular inflammation and atherosclerosis. NF-kB, Nuclear Factor κB; TET2, Ten-eleven translocation 2; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; HMT, Histone lysine methyltransferase; H3K9 demethylation, Demethylation of Histone H3 at Lysine 9; and H3K4m1,…

Figure 4. Main classes and mechanisms of action of epidrugs. The main classes of epigenetic modifiers include DNA methyltransferase inhibitors (DNMTi), histone demethylating inhibitors (HDMi), histone deacetylase activators (and in particular class III, sirtuin-activating compounds, or STACs), histone deacetylase inhibitors (HDACi), histone acetyltransferase inhibitors (HATi) and bromodomain and extra-terminal domain inhibitors (BETi). DNMT, DNA methyltransferase; TET, ten-eleven translocation enzymes; HDM, histone demethylase; HAT, histone acetyltransferase; HDAC, histone deacetylase; SIRT, sirtuins; BRD2, bromodomain 2; and GLP 1, glucagon-like peptide 1.