BACKGROUND: Cellular studies showed that histone methyltransferase Set7 mediates high glucose-induced inflammation via epigenetic regulation of the transcription factor NF-kB. However, the link between Set7 and vascular dysfunction in patients with diabetes remains unknown. This study was designed to investigate whether Set7 contributes to vascular dysfunction in patients with type 2 diabetes (T2DM). METHODS AND RESULTS: -Set7-driven epigenetic changes on NF-kB p65 promoter and expression of NF-kB-dependent genes COX-2 and iNOS were assessed in peripheral blood monocytes (PBM) isolated from 68 subjects (44 T2DM patients and 24 age-matched controls). Brachial artery flow-mediated dilation (FMD), 24-hour urinary levels of 8-isoprostaglandin F2α (8-isoPGF2α) and plasma adhesion molecules ICAM-1 and MCP-1 were also determined. Experiments in human aortic endothelial cells (HAECs) exposed to high glucose were performed to elucidate the mechanisms of Set7-driven inflammation and oxidative stress. Set7 expression increased in PBM from T2DM as compared with controls. T2DM patients showed Set7-dependent monomethylation of lysine 4 of histone 3 (H3K4m1) on NF-kB p65 promoter. This epigenetic signature was associated with upregulation of NF-kB, subsequent transcription of oxidant/inflammatory genes and increased plasma levels of ICAM-1 and MCP-1. Interestingly, we found that Set7 expression significantly correlated with oxidative marker 8-isoPGF2α(r=0.38, p=0.01) and FMD (r= -0.34, p=0.04). In HAECs, silencing of Set7 prevented H3K4m1 and abolished NF-kB-dependent oxidant and inflammatory signalling. CONCLUSIONS: -Set7-induced epigenetic changes contribute to vascular dysfunction in patients with T2DM. Targeting this chromatin modifying enzyme may represent a novel therapeutic approach to prevent atherosclerotic vascular disease in this setting

Adverse Epigenetic Signatures by Histone Methyltransferase Set7 Contribute to Vascular Dysfunction in Patients with Type 2 Diabetes / Paneni, Francesco; Costantino, S; Battista, R; Castello, L; Capretti, Giuliana; Chiandotto, S; Scavone, G; Villano, A; Pitocco, D; Lanza, G; Volpe, Massimo; Lüscher, Tf; Cosentino, Francesco. - In: CIRCULATION, CARDIOVASCULAR GENETICS. - ISSN 1942-325X. - STAMPA. - 8:(2014), pp. 150-158. [10.1161/CIRCGENETICS.114.000671]

Adverse Epigenetic Signatures by Histone Methyltransferase Set7 Contribute to Vascular Dysfunction in Patients with Type 2 Diabetes.

PANENI, FRANCESCO;CAPRETTI, GIULIANA;VOLPE, Massimo;COSENTINO, Francesco
2014

Abstract

BACKGROUND: Cellular studies showed that histone methyltransferase Set7 mediates high glucose-induced inflammation via epigenetic regulation of the transcription factor NF-kB. However, the link between Set7 and vascular dysfunction in patients with diabetes remains unknown. This study was designed to investigate whether Set7 contributes to vascular dysfunction in patients with type 2 diabetes (T2DM). METHODS AND RESULTS: -Set7-driven epigenetic changes on NF-kB p65 promoter and expression of NF-kB-dependent genes COX-2 and iNOS were assessed in peripheral blood monocytes (PBM) isolated from 68 subjects (44 T2DM patients and 24 age-matched controls). Brachial artery flow-mediated dilation (FMD), 24-hour urinary levels of 8-isoprostaglandin F2α (8-isoPGF2α) and plasma adhesion molecules ICAM-1 and MCP-1 were also determined. Experiments in human aortic endothelial cells (HAECs) exposed to high glucose were performed to elucidate the mechanisms of Set7-driven inflammation and oxidative stress. Set7 expression increased in PBM from T2DM as compared with controls. T2DM patients showed Set7-dependent monomethylation of lysine 4 of histone 3 (H3K4m1) on NF-kB p65 promoter. This epigenetic signature was associated with upregulation of NF-kB, subsequent transcription of oxidant/inflammatory genes and increased plasma levels of ICAM-1 and MCP-1. Interestingly, we found that Set7 expression significantly correlated with oxidative marker 8-isoPGF2α(r=0.38, p=0.01) and FMD (r= -0.34, p=0.04). In HAECs, silencing of Set7 prevented H3K4m1 and abolished NF-kB-dependent oxidant and inflammatory signalling. CONCLUSIONS: -Set7-induced epigenetic changes contribute to vascular dysfunction in patients with T2DM. Targeting this chromatin modifying enzyme may represent a novel therapeutic approach to prevent atherosclerotic vascular disease in this setting
2014
01 Pubblicazione su rivista::01a Articolo in rivista
Adverse Epigenetic Signatures by Histone Methyltransferase Set7 Contribute to Vascular Dysfunction in Patients with Type 2 Diabetes / Paneni, Francesco; Costantino, S; Battista, R; Castello, L; Capretti, Giuliana; Chiandotto, S; Scavone, G; Villano, A; Pitocco, D; Lanza, G; Volpe, Massimo; Lüscher, Tf; Cosentino, Francesco. - In: CIRCULATION, CARDIOVASCULAR GENETICS. - ISSN 1942-325X. - STAMPA. - 8:(2014), pp. 150-158. [10.1161/CIRCGENETICS.114.000671]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/648588
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