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.