Matteo Vecellio, 1,2 Francesco Spallotta, 1,2 Simona Nanni, 3 Claudia Colussi, 3 Chiara Cencioni, 2 Anja Derlet, 4 Beatrice Bassetti, 1 Manuela Tilenni, 1 Maria Cristina Carena, 1,2 Antonella Farsetti, 5 Gianluca Sbardella, 6 Sabrina Castellano, 6 Antonello Mai, 7 Fabio Martelli, 8 Giulio Pompilio, 1 Maurizio C. Capogrossi, 9 Alessandra Rossini, 10 Stefanie Dimmeler, 4 Andreas Zeiher, 11 and Carlo Gaetano 2 The Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in the Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients Diabetes 2014;63:2132–2147 | DOI: 10.2337/db13-0731 This study investigates the diabetes-associated alter- ations 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 phosphory- lation at histone H3 serine 10 (H3S10P), decreased differentiation potential, and premature cellular senes- cence. 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 in- creased. These observations were paralleled by a down- regulation of the GCN5-related N-acetyltransferases (GNAT) p300/CBP-associated factor and its isoform 5-a 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 hypermeth- ylation, and recovered D-CMSC proliferation and differen- tiation. These results suggest that epigenetic interventions may reverse alterations in human CMSC obtained from diabetic patients. In recent decades, in association with the progressive increase of the average population age in western countries, type 2 1 Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Milan, Italy 2 Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany 3 Institute of Medical Pathology, Catholic University of Rome, Policlinico A. Gemelli, Rome, Italy 4 Institute of Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany 5 Consiglio Nazionale delle Ricerche, Institute of Cellular Biology and Neurobiology, Rome, Italy 6 Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Fisciano (SA), Italy 7 Department of Drug Chemistry and Technology, University of Rome, Rome, Italy 8 Istituto di Ricovero e Cura a Carattere Scienti fi co Policlinico San Donato, Laboratorio di Cardiologia Molecolare, San Donato Milanese, Milan, Italy 9 Laboratorio di Patologia Vascolare, Istituto Dermopatico dell ’ Immacolata, Rome, Italy 10 Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy 11 Internal Medicine Clinic III, Department of Cardiology, Goethe University, Frankfurt am Main, Germany Corresponding author: Carlo Gaetano, carlo.gaetano@gmail.com or gaetano@ em.uni-frankfurt.de. Received 7 May 2013 and accepted 14 January 2014. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0731/-/DC1. M.V., F.S., and S.N. contributed equally to this work. M.V. and M.C.Car. are currently af filiated 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. © 2014 by the American Diabetes Association. See http://creativecommons.org /licenses/by-nc-nd/3.0/ for details. See accompanying article, p. 1841. 2132 Diabetes Volume 63, June 2014 COMPLICATIONS