This study investigates the diabetes-associated alterations present in cardiac mesenchymal cells (CMSC) obtained from normoglycaemic (ND-CMSC) and Type-2 diabetes patients (D-CMSC), identifying the histone acetylase (HAT) activator pentadecylidenemalonate 1b (SPV106) as 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 HAT activity. DNA CpG island hyper methylation was detected at promoters of genes involved in cell growth control and genomic stability. Remarkably, treatment with the GNAT pro-activator SPV106, restored normal levels of H3K9Ac and H3K14Ac, reduced DNA CpG hyper methylation 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.
§ current address: University of Oxford, Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Windmill Road, Oxford OX3 7LD, UK.
# These authors equally contributed to this work.
- Received May 7, 2013.
- Accepted January 14, 2014.
- © 2014 by the American Diabetes Association.
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