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.

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

SBARDELLA, Gianluca;CASTELLANO, Sabrina;
2014

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.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4266853
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 27
  • Scopus 55
  • ???jsp.display-item.citation.isi??? 53
social impact