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

Abstract

T ype 2 diabetes mellitus (T2DM) is associated with increased risk of micro and macrovascular complications and ≈2-fold greater risk of mortality when compared with the general population.1,2 Advances in therapy have reduced morbidity and mortality in patients with T2DM. However, cardiovascular risk is far to be eradicated, and mechanism-based therapeutic approaches are needed. 3,4 In patients with diabetes mellitus, high-glucose levels trigger endothelial inflammation, mitochondrial oxidative stress, and reduced availability of nitric oxide, a key effector of vascular health. 3,5 This chain of events favors the development of coronary atherosclerotic lesions, as well as microvascular disease. 4 Although the link between diabetes mellitus and atherosclerosis is well established, a better comprehension of the underlying mechanisms is of utmost importance to identify novel molecular targets. Epigenetic modifications are emerging as key players in cardiovascular disease.6 Acetylation and methylation occurring at DNA/histone complexes significantly alter gene transcription 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 mellitus remains unknown. This study was designed to investigate whether Set7 contributes to vascular dysfunction in patients with type 2 diabetes mellitus (T2DM). Methods and Results-Set7-driven epigenetic changes on NF-kB p65 promoter and expression of NF-kB-dependent genes, cyclooxygenase 2 and inducible endothelial nitric oxide synthase, were assessed in peripheral blood mononuclear cells isolated from 68 subjects (44 patients with T2DM and 24 age-matched controls). Brachial artery flow-mediated dilation, 24-hour urinary levels of 8-isoprostaglandin F 2α , and plasma adhesion molecules, intercellular cell adhesion molecule-1 and monocyte chemoattractant protein-1, were also determined. Experiments in human aortic endothelial cells exposed to high glucose were performed to elucidate the mechanisms of Set7-driven inflammation and oxidative stress. Set7 expression increased in peripheral blood mononuclear cells from patients with T2DM when compared with controls.Patients with T2DM showed Set7-dependent monomethylation of lysine 4 of histone 3 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 intercellular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Interestingly, we found that Set7 expression significantly correlated with oxidative marker 8-isoprostaglandin F 2α (r=0.38; P=0.01) and flow-mediated dilation (r=−0.34; P=0.04). In human aortic endothelial cells, silencing of Set7 prevented monomethylation of lysine 4 of histone 3 and abolished NF-kB-dependent oxidant and inflammatory signaling. Conclusions-Set7-induced epigenetic changes contribute to...

Epigenetic assays for chemical biology and drug discovery

“…Specific examples of proteins in this class include lysine-specific demethylase (LSD) and the Jumonji C domain-containing histone demethylase (JHDM). This protein target class has been implicated in cancer [136], diabetes [137] and cardiovascular disease [138]. …”

Diabetes propels the risk for cardiovascular disease: sweet monocytes becoming aggressive?

“…Importantly, monocytes from uncontrolled type 1 diabetes patients showed an increased acetylation of H3K9Ac in promoters of genes related to inflammatory pathways [64]. In addition, the methyltransferase Set7 may play a role in epigenetic regulation of NF-κB under hyperglycemic conditions, since Set7 is upregulated in monocytes from T2D and associates with fasting plasma glucose and HbA1c, as well as H3K4m1 of the NF-κB promoter region and expression of NF-κB target genes [65]. Evidence for persistence of epigenetic changes over time has only recently been shown by measuring epigenetic DNA methylation alterations in whole blood derived from a DCCT/EDIC subcohort, while comparing genomic DNA from intensively and conventionally treated patients before and after the EDIC follow-up [66].…”

Hyperglycemia-associated alterations in cellular signaling and dysregulated mitochondrial bioenergetics in human metabolic disorders

“…Subsequent work suggests that AGEs themselves are capable of activating RAGE gene expression via NF-kB-mediated processes, resulting in the exacerbation of diabetic microvascular damage [17]. Interestingly, the epigenetic signature of the promotor region of the NF-kB subunit gene RelA/p65/NF-kB3 from peripheral blood mononuclear cells isolated from patients with type 2 diabetes was functionally associated with enhanced transcription of pro-oxidant/inflammatory genes and subsequent vascular damage [18]. The epigenetically mediated upregulation of RelA/p65/NF-kB3 was subsequently linked to the deleterious effects of increased plasma levels of intercellular cell adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1.…”