The histone acetylase activator pentadecylidenemalonate 1b rescues proliferation and differentiation in the human cardiac mesenchymal cells of type 2 diabetic patients

Matteo Vecellio, Francesco Spallotta, Simona Nanni, Claudia Colussi, 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

Research output: Contribution to journalArticle

Abstract

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 languageEnglish
Pages (from-to)2132-2147
Number of pages16
JournalDiabetes
Volume63
Issue number6
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Vecellio, M., Spallotta, F., Nanni, S., Colussi, C., Cencioni, C., Derlet, A., Bassetti, B., Tilenni, M., Carena, M. C., Farsetti, A., Sbardella, G., Castellano, S., Mai, A., Martelli, F., Pompilio, G., Capogrossi, M. C., Rossini, A., Dimmeler, S., Zeiher, A., & Gaetano, C. (2014). The histone acetylase activator pentadecylidenemalonate 1b rescues proliferation and differentiation in the human cardiac mesenchymal cells of type 2 diabetic patients. Diabetes, 63(6), 2132-2147. https://doi.org/10.2337/db13-0731