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Adverse Epigenetic signatures by histone methyltransferase set7 contribute to vascular dysfunction in patients with type 2 diabetes


Paneni, Francesco; Costantino, Sarah; Battista, Rodolfo; Castello, Lorenzo; Capretti, Giuliana; Chiandotto, Sergio; Scavone, Giuseppe; Villano, Angelo; Pitocco, Dario; Lanza, Gaetano; Volpe, Massimo; Lüscher, Thomas F; Cosentino, Francesco (2015). Adverse Epigenetic signatures by histone methyltransferase set7 contribute to vascular dysfunction in patients with type 2 diabetes. Circulation. Cardiovascular Genetics, 8(1):150-158.

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.

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.

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14 citations in Web of Science®
12 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2015
Deposited On:12 Feb 2015 10:50
Last Modified:05 Apr 2016 18:59
Publisher:American Heart Association
ISSN:1942-3268
Publisher DOI:https://doi.org/10.1161/CIRCGENETICS.114.000671
PubMed ID:25472959

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