The Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients

Simona Nanni, Matteo Vecellio, Francesco Spallotta, Chiara Cencioni, Anja Derlet, Beatrice Bassetti, Manuela Tilenni, Maria Cristina Carena, Antonella Farsetti, Gianluca Sbardella, Sabrina Castellano, Antonello Mai, Fabio Martelli, Giulio Pompilio, Maurizio C. Capogrossi, Alessandra Rossini, Stefanie Dimmeler, Andreas Zeiher, Carlo Gaetano

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

45 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
pagine (da-a)2132-2147
Numero di pagine16
RivistaDiabetes
DOI
Stato di pubblicazionePubblicato - 2014

Keywords

  • epigenetics

Fingerprint Entra nei temi di ricerca di 'The Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients'. Insieme formano una fingerprint unica.

Cita questo