PMID- 25472959
OWN - NLM
STAT- MEDLINE
DCOM- 20151207
LR  - 20150218
IS  - 1942-3268 (Electronic)
IS  - 1942-3268 (Linking)
VI  - 8
IP  - 1
DP  - 2015 Feb
TI  - Adverse epigenetic signatures by histone methyltransferase Set7 contribute to 
      vascular dysfunction in patients with type 2 diabetes mellitus.
PG  - 150-8
LID - 10.1161/CIRCGENETICS.114.000671 [doi]
AB  - 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 F2alpha, 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 F2alpha (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.
CI  - (c) 2014 American Heart Association, Inc.
FAU - Paneni, Francesco
AU  - Paneni F
AD  - 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 Zurich, Zurich, Switzerland (T.F.L.). francesco.cosentino@ki.se.
FAU - Costantino, Sarah
AU  - Costantino S
AD  - 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 Zurich, Zurich, Switzerland (T.F.L.).
FAU - Battista, Rodolfo
AU  - Battista R
AD  - 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 Zurich, Zurich, Switzerland (T.F.L.).
FAU - Castello, Lorenzo
AU  - Castello L
AD  - 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 Zurich, Zurich, Switzerland (T.F.L.).
FAU - Capretti, Giuliana
AU  - Capretti G
AD  - 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 Zurich, Zurich, Switzerland (T.F.L.).
FAU - Chiandotto, Sergio
AU  - Chiandotto S
AD  - 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 Zurich, Zurich, Switzerland (T.F.L.).
FAU - Scavone, Giuseppe
AU  - Scavone G
AD  - 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 Zurich, Zurich, Switzerland (T.F.L.).
FAU - Villano, Angelo
AU  - Villano A
AD  - 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 Zurich, Zurich, Switzerland (T.F.L.).
FAU - Pitocco, Dario
AU  - Pitocco D
AD  - 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 Zurich, Zurich, Switzerland (T.F.L.).
FAU - Lanza, Gaetano
AU  - Lanza G
AD  - 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 Zurich, Zurich, Switzerland (T.F.L.).
FAU - Volpe, Massimo
AU  - Volpe M
AD  - 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 Zurich, Zurich, Switzerland (T.F.L.).
FAU - Luscher, Thomas F
AU  - Luscher TF
AD  - 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 Zurich, Zurich, Switzerland (T.F.L.).
FAU - Cosentino, Francesco
AU  - Cosentino F
AD  - 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 Zurich, Zurich, Switzerland (T.F.L.).
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141203
PL  - United States
TA  - Circ Cardiovasc Genet
JT  - Circulation. Cardiovascular genetics
JID - 101489144
RN  - 0 (RELA protein, human)
RN  - 0 (Transcription Factor RelA)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
RN  - EC 2.1.1.43 (SETD7 protein, human)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Cells, Cultured
MH  - Diabetes Mellitus, Type 2/*enzymology/genetics
MH  - Diabetic Angiopathies/*enzymology/genetics
MH  - Endothelial Cells/*enzymology
MH  - *Epigenesis, Genetic
MH  - Female
MH  - Histone-Lysine N-Methyltransferase/genetics/*metabolism
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Promoter Regions, Genetic
MH  - Transcription Factor RelA/genetics/metabolism
OTO - NOTNLM
OT  - diabetes mellitus
OT  - epigenomics
OT  - inflammation
OT  - oxidative stress
EDAT- 2014/12/05 06:00
MHDA- 2015/12/15 06:00
CRDT- 2014/12/05 06:00
PHST- 2014/12/05 06:00 [entrez]
PHST- 2014/12/05 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
AID - CIRCGENETICS.114.000671 [pii]
AID - 10.1161/CIRCGENETICS.114.000671 [doi]
PST - ppublish
SO  - Circ Cardiovasc Genet. 2015 Feb;8(1):150-8. doi: 10.1161/CIRCGENETICS.114.000671. 
      Epub 2014 Dec 3.