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This study investigates the diabetes-associated alterations present in cardiac mesenchymal cells (CMSC) obtained from normoglycemic (ND-CMSC) and type 2 diabetic 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 (H3K9Ac) and lysine 14 (H3K14Ac) was decreased, whereas the trimethylation of H3K9Ac and lysine 27 significantly increased. These observations were paralleled by a downregulation of the GCN5-related N-acetyltransferases (GNAT) p300/CBP-associated factor and its isoform 5-α general control of amino acid synthesis (GCN5a), determining a relative decrease in total HAT activity. DNA CpG island hypermethylation was detected at promoters of genes involved in cell growth control and genomic stability. Remarkably, treatment with the GNAT proactivator SPV106 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 CMSC obtained from diabetic patients.

Original publication

DOI

10.2337/db13-0731

Type

Journal article

Journal

Diabetes

Publication Date

06/2014

Volume

63

Pages

2132 - 2147

Addresses

Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Milan, ItalyDivision of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany.

Keywords

Myocytes, Cardiac, Humans, Cardiomyopathies, Diabetic Angiopathies, Diabetes Mellitus, Type 2, Malonates, Histones, Blotting, Western, Immunoprecipitation, Cell Differentiation, Cell Proliferation, DNA Methylation, Enzyme Activation, CpG Islands, Phosphorylation, Middle Aged, Female, Male, p300-CBP Transcription Factors, Histone Acetyltransferases, Promoter Regions, Genetic, Mesenchymal Stromal Cells