Introduction: optimal glycemic control (OGC) has failed to improve cardiovascular outcomes in patients with diabetes. We have recently reported that epigenetic regulation of the mitochondrial adaptor p66Shc, critically involved in oxidative stress, accounts for persistent endothelial dysfunction in diabetic mice with OGC. Hypothesis: we investigate whether epigenetic changes of p66Shc contribute to residual oxidative stress and vascular disease in patients with type 2 diabetes (T2DM). Methods: 7 patients with newly-diagnosed T2DM and 7 age-matched controls were studied (age 46±3 vs. 42±7 years, p=NS). After the enrolment, T2DM patients were assigned to OGC for 6 months. Glycated haemoglobin (HbA1c) and continuous blood glucose monitoring (CGM) were used as markers of glycemic control. At baseline and follow-up, patients underwent flow-mediated vasodilation (FMD) of the brachial artery. Urinary levels of 8-isoprostaglandinF2α (8-isoPGF2α) were measured as a marker of oxidative stress. p66Shc mRNA expression was assessed from peripheral blood monocytes (PBM). Chromatin immunoprecipitation (ChIP) and real time PCR were performed to investigate histone acetylation and DNA methylation of p66Shc promoter, respectively. Results: Hb1Ac (9.4±2 vs. 6.9±1%, p<0.01) and CGM (235±25 vs. 131±28 mg/dl, p<0.05) confirmed OGC in T2DM patients. As compared with controls. T2DM patients showed blunted FMD (6.8±1.9 vs. 8.6±1.4 %, p<0.05), increased urinary 8-isoPGF2α levels (295±100 vs. 33±9 pg/mL, p<0.05) and p66Shc gene upregulation (0.18±0.06 vs.0.05±0.03 AU, p<0.05). However, OGC did not rescue endothelial function (FMD 6.9±1.7 vs. 6.8±1.9%, p=NS), oxidative stress (295±100 vs. 292±85 pg/ml, p=NS) and p66Shc upregulation (0.18±0.06 vs.0.22±0.1, AU, p=NS). T2DM patients showed lysine 14 acetylation of histone 3 binding p66Shc promoter and hypomethylation of CpG dinucleotides, two critical epigenetic markers favouring p66Shc overexpression. Interestingly, these epigenetic changes remained despite OGC and correlated with persistent endothelial dysfunction and oxidative stress. Conclusions: Epigenetic regulation of p66Shc gene may contribute to the residual burden of vascular disease in T2DM individuals with OGC.
Epigenetic signatures of p66Shc promoter contribute to persistent endothelial dysfunction in type 2 diabetics with optimal glycemic control / Francesco, Paneni; Sarah, Costantino; Lorenzo, Castello; Rodolfo, Battista; Capretti, Giuliana; Sergio, Chiandotto; Thomas, Lüscher; Gaetano, Lanza; Volpe, Massimo; Cosentino, Francesco. - In: CIRCULATION. - ISSN 0009-7322. - 128:(2013). (Intervento presentato al convegno American Heart Association (AHA) 2013 Scientific Sessions tenutosi a Dallas, Texas nel 16-20 novembre 2013).
Epigenetic signatures of p66Shc promoter contribute to persistent endothelial dysfunction in type 2 diabetics with optimal glycemic control
CAPRETTI, GIULIANA;VOLPE, Massimo;COSENTINO, Francesco
2013
Abstract
Introduction: optimal glycemic control (OGC) has failed to improve cardiovascular outcomes in patients with diabetes. We have recently reported that epigenetic regulation of the mitochondrial adaptor p66Shc, critically involved in oxidative stress, accounts for persistent endothelial dysfunction in diabetic mice with OGC. Hypothesis: we investigate whether epigenetic changes of p66Shc contribute to residual oxidative stress and vascular disease in patients with type 2 diabetes (T2DM). Methods: 7 patients with newly-diagnosed T2DM and 7 age-matched controls were studied (age 46±3 vs. 42±7 years, p=NS). After the enrolment, T2DM patients were assigned to OGC for 6 months. Glycated haemoglobin (HbA1c) and continuous blood glucose monitoring (CGM) were used as markers of glycemic control. At baseline and follow-up, patients underwent flow-mediated vasodilation (FMD) of the brachial artery. Urinary levels of 8-isoprostaglandinF2α (8-isoPGF2α) were measured as a marker of oxidative stress. p66Shc mRNA expression was assessed from peripheral blood monocytes (PBM). Chromatin immunoprecipitation (ChIP) and real time PCR were performed to investigate histone acetylation and DNA methylation of p66Shc promoter, respectively. Results: Hb1Ac (9.4±2 vs. 6.9±1%, p<0.01) and CGM (235±25 vs. 131±28 mg/dl, p<0.05) confirmed OGC in T2DM patients. As compared with controls. T2DM patients showed blunted FMD (6.8±1.9 vs. 8.6±1.4 %, p<0.05), increased urinary 8-isoPGF2α levels (295±100 vs. 33±9 pg/mL, p<0.05) and p66Shc gene upregulation (0.18±0.06 vs.0.05±0.03 AU, p<0.05). However, OGC did not rescue endothelial function (FMD 6.9±1.7 vs. 6.8±1.9%, p=NS), oxidative stress (295±100 vs. 292±85 pg/ml, p=NS) and p66Shc upregulation (0.18±0.06 vs.0.22±0.1, AU, p=NS). T2DM patients showed lysine 14 acetylation of histone 3 binding p66Shc promoter and hypomethylation of CpG dinucleotides, two critical epigenetic markers favouring p66Shc overexpression. Interestingly, these epigenetic changes remained despite OGC and correlated with persistent endothelial dysfunction and oxidative stress. Conclusions: Epigenetic regulation of p66Shc gene may contribute to the residual burden of vascular disease in T2DM individuals with OGC.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
