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

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

  • Diabetes. 2014 Jun;63(6):2132-47. doi: 10.2337/db13-0731.
Matteo Vecellio 1,  Francesco Spallotta 1,  Simona Nanni 2,  Claudia Colussi 2,  Chiara Cencioni 3,  Anja Derlet 4,  Beatrice Bassetti 5,  Manuela Tilenni 5,  Maria Cristina Carena 1,  Antonella Farsetti 6,  Gianluca Sbardella 7,  Sabrina Castellano 7,  Antonello Mai 8,  Fabio Martelli 9,  Giulio Pompilio 5,  Maurizio C Capogrossi 10,  Alessandra Rossini 11,  Stefanie Dimmeler 4,  Andreas Zeiher 12,  Carlo Gaetano 13
Affiliations

Affiliations

  • 1 Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Milan, ItalyDivision of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany.
  • 2 Institute of Medical Pathology, Catholic University of Rome, Policlinico A. Gemelli, Rome, Italy.
  • 3 Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany.
  • 4 Institute of Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany.
  • 5 Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Milan, Italy.
  • 6 Consiglio Nazionale delle Ricerche, Institute of Cellular Biology and Neurobiology, Rome, Italy.
  • 7 Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Fisciano (SA), Italy.
  • 8 Department of Drug Chemistry and Technology, University of Rome, Rome, Italy.
  • 9 Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Donato, Laboratorio di Cardiologia Molecolare, San Donato Milanese, Milan, Italy.
  • 10 Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Rome, Italy.
  • 11 Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy.
  • 12 Internal Medicine Clinic III, Department of Cardiology, Goethe University, Frankfurt am Main, Germany.
  • 13 Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany carlo.gaetano@gmail.com gaetano@em.uni-frankfurt.de.
PMID: 24458358 DOI: 10.2337/db13-0731
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.

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