Chemical Activation of Lysine Acetylation Rescues Proliferation and Differentiation in Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients

In this study, we investigated diabetes-associated alterations present in cardiac mesenchymal cells (CMSC) obtained from normoglycaemic (ND-CMSC) and Type-2 Diabetes patients (D-CMSC), identifying a potential pharmacological intervention to restore cellular function. D-CMSC were characterized by a reduced proliferation rate, diminished phosphorylation at histone H3 Serine 10 (H3S10P), decreased differentiation potential and premature cellular senescence. A global histone code profiling of D-CMSC revealed that acetylation on histone H3 Lysine 9 and Lysine 14 (H3K9Ac; H3K14Ac) was decreased while the trimethylation of histone H3 Lysine 9 and Lysine 27 (H3K9Me3; H3K27Me3) significantly increased. These observations were paralleled by a down-regulation of the GCN5-Related N-acetyltransferases (GNAT) p300/CBP associated factor (PCAF) and its isoform 5-alpha General Control of Amino Acid Synthesis (GCN5a), determining a relative decrease in total histone acetyl-transferase (HAT) activity. DNA CpG island hypermethylation was also detected at promoters of genes involved in cell proliferation and genomic DNA stability. Remarkably, treatment with the GNAT pro-activation compound SPV106, able to activate PCAF/GCN5A, restored normal levels of H3K9Ac and H3K14Ac, reduced DNA CpG hypermethylation and recovered D-CMSC proliferation and differentiation. These results suggest that epigenetic interventions may reverse alterations in human cardiac mesenchymal cells obtained from diabetic patients.