title: 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).
  
  
  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.affiliation: 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Paneni
authors.affiliation: 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.).
authors.forename: Sarah
authors.initials: S
authors.lastname: Costantino
authors.affiliation: 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.).
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Battista
authors.affiliation: 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.).
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Castello
authors.affiliation: 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.).
authors.forename: Giuliana
authors.initials: G
authors.lastname: Capretti
authors.affiliation: 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.).
authors.forename: Sergio
authors.initials: S
authors.lastname: Chiandotto
authors.affiliation: 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.).
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Scavone
authors.affiliation: 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.).
authors.forename: Angelo
authors.initials: A
authors.lastname: Villano
authors.affiliation: 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.).
authors.forename: Dario
authors.initials: D
authors.lastname: Pitocco
authors.affiliation: 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.).
authors.forename: Gaetano
authors.initials: G
authors.lastname: Lanza
authors.affiliation: 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.).
authors.forename: Massimo
authors.initials: M
authors.lastname: Volpe
authors.affiliation: 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.).
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.affiliation: 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.).
authors.forename: Francesco
authors.initials: F
authors.lastname: Cosentino
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics; D003925:Diabetic Angiopathies / Q000201:enzymology* / Q000235:genetics; D042783:Endothelial Cells / Q000201:enzymology*; D044127:Epigenesis, Genetic; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism
chemical_list: C498143:RELA protein, human; D051996:Transcription Factor RelA; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human
keywords: diabetes mellitus; epigenomics; inflammation; oxidative stress