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

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

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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