Francesco Paneni1, Sarah Costantino2, Rodolfo Battista2, Lorenzo Castello2, Giuliana Capretti2, Sergio Chiandotto2, Giuseppe Scavone2, Angelo Villano2, Dario Pitocco2, Gaetano Lanza2, Massimo Volpe2, Thomas F Lüscher2, Francesco Cosentino2. 1. From the Cardiology Unit, Department of Medicine Solna, Karolinska University Hospital, Stockholm, Sweden (F.P., S.C., F.C.); Department of Internal Medicine, Civil Hospital, Sora, Italy (R.B.); Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (L.C., G.C., S.C., M.V.); Diabetes Care Unit, Department of Internal Medicine (G.S., D.P.), Department of Cardiovascular Medicine (A.V., G.L.), Catholic University, Rome, Italy; IRCCS Neuromed, Pozzilli, Italy (M.V.); and Department of Cardiology, Cardiovascular Research, Institute of Physiology, University Hospital of Zürich, Zürich, Switzerland (T.F.L.). francesco.cosentino@ki.se. 2. From the Cardiology Unit, Department of Medicine Solna, Karolinska University Hospital, Stockholm, Sweden (F.P., S.C., F.C.); Department of Internal Medicine, Civil Hospital, Sora, Italy (R.B.); Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (L.C., G.C., S.C., M.V.); Diabetes Care Unit, Department of Internal Medicine (G.S., D.P.), Department of Cardiovascular Medicine (A.V., G.L.), Catholic University, Rome, Italy; IRCCS Neuromed, Pozzilli, Italy (M.V.); and Department of Cardiology, Cardiovascular Research, Institute of Physiology, University Hospital of Zürich, Zürich, Switzerland (T.F.L.).
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.
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: Andrew S Kimball; Amrita Joshi; William F Carson; Anna E Boniakowski; Matthew Schaller; Ronald Allen; Jennifer Bermick; Frank M Davis; Peter K Henke; Charles F Burant; Steve L Kunkel; Katherine A Gallagher Journal: Diabetes Date: 2017-06-29 Impact factor: 9.461