The Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in the Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients
- Matteo Vecellio1,2,
- Francesco Spallotta1,2,
- Simona Nanni3,
- Claudia Colussi3,
- Chiara Cencioni2,
- Anja Derlet4,
- Beatrice Bassetti1,
- Manuela Tilenni1,
- Maria Cristina Carena1,2,
- Antonella Farsetti5,
- Gianluca Sbardella6,
- Sabrina Castellano6,
- Antonello Mai7,
- Fabio Martelli8,
- Giulio Pompilio1,
- Maurizio C. Capogrossi9,
- Alessandra Rossini10,
- Stefanie Dimmeler4,
- Andreas Zeiher11 and
- Carlo Gaetano2⇑
- 1Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Milan, Italy
- 2Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany
- 3Institute of Medical Pathology, Catholic University of Rome, Policlinico A. Gemelli, Rome, Italy
- 4Institute of Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany
- 5Consiglio Nazionale delle Ricerche, Institute of Cellular Biology and Neurobiology, Rome, Italy
- 6Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Fisciano (SA), Italy
- 7Department of Drug Chemistry and Technology, University of Rome, Rome, Italy
- 8Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Donato, Laboratorio di Cardiologia Molecolare, San Donato Milanese, Milan, Italy
- 9Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’Immacolata, Rome, Italy
- 10Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy
- 11Internal Medicine Clinic III, Department of Cardiology, Goethe University, Frankfurt am Main, Germany
- Corresponding author: Carlo Gaetano, or .
M.V., F.S., and S.N. contributed equally to this work.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0731/-/DC1.
M.V. and M.C.Car. are currently affiliated with the University of Oxford, Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Oxford U.K.
See accompanying article, p. 1841.
- Received May 7, 2013.
- Accepted January 14, 2014.
- © 2014 by the American Diabetes Association.
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