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

Dario Pitocco, Gaetano Antonio Lanza, Massimo Volpe, Francesco Cosentino, Francesco Paneni, Sarah Costantino, Rodolfo Battista, Lorenzo Castello, Giuliana Capretti, Sergio Chiandotto, Thomas F. Lüscher

Risultato della ricerca: Contributo in rivistaArticolo in rivista

80 Citazioni (Scopus)

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 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 F2α, 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 F2α (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 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.
Lingua originaleEnglish
pagine (da-a)150-158
Numero di pagine9
RivistaCIRCULATION, CARDIOVASCULAR GENETICS
Volume8
DOI
Stato di pubblicazionePubblicato - 2015

Keywords

  • Adult
  • Aged
  • Cardiology and Cardiovascular Medicine
  • Cells, Cultured
  • Diabetes Mellitus, Type 2
  • Diabetes mellitus
  • Diabetic Angiopathies
  • Endothelial Cells
  • Epigenesis, Genetic
  • Epigenomics
  • Female
  • Genetics
  • Genetics (clinical)
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Inflammation
  • Male
  • Middle Aged
  • Oxidative stress
  • Promoter Regions, Genetic
  • Transcription Factor RelA

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