The histone acetylase activator pentadecylidenemalonate 1b rescues proliferation and differentiation in the human cardiac mesenchymal cells of type 2 diabetic patients.
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.
Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Milan, ItalyDivision of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany.
Matteo
M
Vecellio
Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Milan, ItalyDivision of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany.
Francesco
F
Spallotta
Institute of Medical Pathology, Catholic University of Rome, Policlinico A. Gemelli, Rome, Italy.
Simona
S
Nanni
Institute of Medical Pathology, Catholic University of Rome, Policlinico A. Gemelli, Rome, Italy.
Claudia
C
Colussi
Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany.
Chiara
C
Cencioni
Institute of Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany.
Anja
A
Derlet
Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Milan, Italy.
Beatrice
B
Bassetti
Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Milan, Italy.
Manuela
M
Tilenni
Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Milan, ItalyDivision of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany.
Maria Cristina
MC
Carena
Consiglio Nazionale delle Ricerche, Institute of Cellular Biology and Neurobiology, Rome, Italy.
Antonella
A
Farsetti
Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Fisciano (SA), Italy.
Gianluca
G
Sbardella
Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Fisciano (SA), Italy.
Sabrina
S
Castellano
Department of Drug Chemistry and Technology, University of Rome, Rome, Italy.
Antonello
A
Mai
Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Donato, Laboratorio di Cardiologia Molecolare, San Donato Milanese, Milan, Italy.
Fabio
F
Martelli
Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Milan, Italy.
Giulio
G
Pompilio
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Rome, Italy.
Maurizio C
MC
Capogrossi
Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy.
Alessandra
A
Rossini
Institute of Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany.
Stefanie
S
Dimmeler
Internal Medicine Clinic III, Department of Cardiology, Goethe University, Frankfurt am Main, Germany.
Andreas
A
Zeiher
Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany carlo.gaetano@gmail.com gaetano@em.uni-frankfurt.de.
Carlo
C
Gaetano
D015153:Blotting, Western; D009202:Cardiomyopathies / Q000188:drug therapy / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D018899:CpG Islands / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D051548:Histone Acetyltransferases / Q000187:drug effects* / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008314:Malonates / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D050880:p300-CBP Transcription Factors / Q000494:pharmacology*; D000099224:p300-CBP-Associated Factor
D051548:Histone Acetyltransferases; D006657:Histones; D008314:Malonates; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C000591545:pentadecylidenemalonate 1b