The Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in the Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients

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-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 hypermethylation, and recovered D-CMSC proliferation and differentiation. 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

Bromodomain inhibitors and cancer therapy: From structures to applications

“…SPV106 has been successfully used in neurological 171 and cardiological 172,173 studies where the acetylation activity of KAT2B was investigated. Moreover, in cardiac mesenchymal cells, SPV106 recovered differentiation and proliferation in patients with diabetes 174 . Additionally, TTK21 was reported as an activator of CBP (KAT3A) and p300 (KAT3B), which was able to promote neurogenesis and increased long-term memory in adult mice 175 .…”

Essential Role of the Zinc Finger Transcription Factor Casz1 for Mammalian Cardiac Morphogenesis and Development

“…Cell Culture and Transfection Conditions-Human cardiac fibroblasts from a normal 18-year-old individual were obtained from a commercial source (Innoprot) and cultured as previously described (21,22). In brief, cells were grown in Iscove's modified Dulbecco's medium (Lonza), supplemented with 20% FBS (Hyclone), 10 ng/ml basic fibroblast growth factor (R&D), 1% penicillin/streptomycin (Thermo Fisher Scientific), and 1% L-glutamine (Lonza).…”

Importance of Metabolic Memory in the Development of Vascular Complications in Diabetic Patients

“…70,71,85-87 Several drugs with a potential capacity to modulate the epigenetic machinery could be suggested as new drugs for the treatment of MetM. 20-23, [87][88][89][90][91] The aim is to rescue the normal conformational structure of chromatin and reverse the changes induced by chronic hyperglycemia. It is believed that these drugs could slow, stop, or even reverse the longterm vascular complications of MetM.…”