Adverse epigenetic signatures by histone methyltransferase Set7 contribute to vascular dysfunction in patients with type 2 diabetes mellitus.

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.

• Authors: Francesco Paneni, Sarah Costantino, Rodolfo Battista, Lorenzo Castello, Giuliana Capretti, Sergio Chiandotto, Giuseppe Scavone, Angelo Villano, Dario Pitocco, Gaetano Lanza, Massimo Volpe, Thomas F Lüscher, Francesco Cosentino
• Journal: Circulation. Cardiovascular genetics (Circ Cardiovasc Genet) Vol. 8 Issue 1 Pg. 150-8 (Feb 2015) ISSN: 1942-3268 [Electronic] United States
• PMID: 25472959 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• RELA protein, human
• Transcription Factor RelA
• Histone-Lysine N-Methyltransferase
• SETD7 protein, human

Topics

• Adult
• Aged
• Cells, Cultured
• Diabetes Mellitus, Type 2 (enzymology, genetics)
• Diabetic Angiopathies (enzymology, genetics)
• Endothelial Cells (enzymology)
• Epigenesis, Genetic
• Female
• Histone-Lysine N-Methyltransferase (genetics, metabolism)
• Humans
• Male
• Middle Aged
• Promoter Regions, Genetic
• Transcription Factor RelA (genetics, metabolism)