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Original Article

Proteome-Based Systems Biology Analysis of the Diabetic Mouse Aorta Reveals Major Changes in Fatty Acid Biosynthesis as Potential Hallmark in Diabetes Mellitus–Associated Vascular DiseaseCLINICAL PERSPECTIVE

Holger Husi, Tom Van Agtmael, William Mullen, Ferdinand H. Bahlmann, Joost P. Schanstra, Antonia Vlahou, Christian Delles, Paul Perco, Harald Mischak
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https://doi.org/10.1161/CIRCGENETICS.113.000196
Circulation: Genomic and Precision Medicine. 2014;7:161-170
Originally published February 26, 2014
Holger Husi
From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK (H.H., T.V.A., W.M., C.D., H.M.); Universitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.H.B.); Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Université Toulouse III Paul-Sabatier, Toulouse, France (J.P.S.); Biomedical Research Foundation, Academy of Athens, Athens, Greece (A.V.); School of Biomedical and Biological Sciences, Plymouth University, Plymouth, UK (A.V.); Emergentec Biodevelopment GmbH, Vienna, Austria (P.P.); and Mosaiques Diagnostics GmbH, Hannover, Germany (H.M.).
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Tom Van Agtmael
From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK (H.H., T.V.A., W.M., C.D., H.M.); Universitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.H.B.); Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Université Toulouse III Paul-Sabatier, Toulouse, France (J.P.S.); Biomedical Research Foundation, Academy of Athens, Athens, Greece (A.V.); School of Biomedical and Biological Sciences, Plymouth University, Plymouth, UK (A.V.); Emergentec Biodevelopment GmbH, Vienna, Austria (P.P.); and Mosaiques Diagnostics GmbH, Hannover, Germany (H.M.).
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William Mullen
From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK (H.H., T.V.A., W.M., C.D., H.M.); Universitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.H.B.); Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Université Toulouse III Paul-Sabatier, Toulouse, France (J.P.S.); Biomedical Research Foundation, Academy of Athens, Athens, Greece (A.V.); School of Biomedical and Biological Sciences, Plymouth University, Plymouth, UK (A.V.); Emergentec Biodevelopment GmbH, Vienna, Austria (P.P.); and Mosaiques Diagnostics GmbH, Hannover, Germany (H.M.).
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Ferdinand H. Bahlmann
From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK (H.H., T.V.A., W.M., C.D., H.M.); Universitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.H.B.); Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Université Toulouse III Paul-Sabatier, Toulouse, France (J.P.S.); Biomedical Research Foundation, Academy of Athens, Athens, Greece (A.V.); School of Biomedical and Biological Sciences, Plymouth University, Plymouth, UK (A.V.); Emergentec Biodevelopment GmbH, Vienna, Austria (P.P.); and Mosaiques Diagnostics GmbH, Hannover, Germany (H.M.).
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Joost P. Schanstra
From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK (H.H., T.V.A., W.M., C.D., H.M.); Universitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.H.B.); Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Université Toulouse III Paul-Sabatier, Toulouse, France (J.P.S.); Biomedical Research Foundation, Academy of Athens, Athens, Greece (A.V.); School of Biomedical and Biological Sciences, Plymouth University, Plymouth, UK (A.V.); Emergentec Biodevelopment GmbH, Vienna, Austria (P.P.); and Mosaiques Diagnostics GmbH, Hannover, Germany (H.M.).
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Antonia Vlahou
From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK (H.H., T.V.A., W.M., C.D., H.M.); Universitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.H.B.); Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Université Toulouse III Paul-Sabatier, Toulouse, France (J.P.S.); Biomedical Research Foundation, Academy of Athens, Athens, Greece (A.V.); School of Biomedical and Biological Sciences, Plymouth University, Plymouth, UK (A.V.); Emergentec Biodevelopment GmbH, Vienna, Austria (P.P.); and Mosaiques Diagnostics GmbH, Hannover, Germany (H.M.).
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Christian Delles
From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK (H.H., T.V.A., W.M., C.D., H.M.); Universitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.H.B.); Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Université Toulouse III Paul-Sabatier, Toulouse, France (J.P.S.); Biomedical Research Foundation, Academy of Athens, Athens, Greece (A.V.); School of Biomedical and Biological Sciences, Plymouth University, Plymouth, UK (A.V.); Emergentec Biodevelopment GmbH, Vienna, Austria (P.P.); and Mosaiques Diagnostics GmbH, Hannover, Germany (H.M.).
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Paul Perco
From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK (H.H., T.V.A., W.M., C.D., H.M.); Universitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.H.B.); Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Université Toulouse III Paul-Sabatier, Toulouse, France (J.P.S.); Biomedical Research Foundation, Academy of Athens, Athens, Greece (A.V.); School of Biomedical and Biological Sciences, Plymouth University, Plymouth, UK (A.V.); Emergentec Biodevelopment GmbH, Vienna, Austria (P.P.); and Mosaiques Diagnostics GmbH, Hannover, Germany (H.M.).
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Harald Mischak
From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK (H.H., T.V.A., W.M., C.D., H.M.); Universitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.H.B.); Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Université Toulouse III Paul-Sabatier, Toulouse, France (J.P.S.); Biomedical Research Foundation, Academy of Athens, Athens, Greece (A.V.); School of Biomedical and Biological Sciences, Plymouth University, Plymouth, UK (A.V.); Emergentec Biodevelopment GmbH, Vienna, Austria (P.P.); and Mosaiques Diagnostics GmbH, Hannover, Germany (H.M.).
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Abstract

Background—Macrovascular complications of diabetes mellitus are a major risk factor for cardiovascular morbidity and mortality. Currently, studies only partially described the molecular pathophysiology of diabetes mellitus–associated effects on vasculature. However, better understanding of systemic effects is essential in unraveling key molecular events in the vascular tissue responsible for disease onset and progression.

Methods and Results—Our overall aim was to get an all-encompassing view of diabetes mellitus–induced key molecular changes in the vasculature. An integrative proteomic and bioinformatics analysis of data from aortic vessels in the low-dose streptozotocin-induced diabetic mouse model (10 animals) was performed. We observed pronounced dysregulation of molecules involved in myogenesis, vascularization, hypertension, hypertrophy (associated with thickening of the aortic wall), and a substantial reduction of fatty acid storage. A novel finding is the pronounced downregulation of glycogen synthase kinase-3β (Gsk3β) and upregulation of molecules linked to the tricarboxylic acid cycle (eg, aspartate aminotransferase [Got2] and hydroxyacid-oxoacid transhydrogenase [Adhfe1]). In addition, pathways involving primary alcohols and amino acid breakdown are altered, potentially leading to ketone-body production. A number of these findings were validated immunohistochemically. Collectively, the data support the hypothesis that in this diabetic model, there is an overproduction of ketone-bodies within the vessels using an alternative tricarboxylic acid cycle-associated pathway, ultimately leading to the development of atherosclerosis.

Conclusions—Streptozotocin-induced diabetes mellitus in animals leads to a reduction of fatty acid biosynthesis and an upregulation of an alternative ketone-body formation pathway. This working hypothesis could form the basis for the development of novel therapeutic intervention and disease management approaches.

  • aorta
  • blood supply
  • diabetes mellitus
  • ketone bodies
  • muscles
  • proteomics
  • smooth muscle
  • systems biology
  • Received February 21, 2013.
  • Accepted January 29, 2014.
  • © 2014 American Heart Association, Inc.
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April 2014, Volume 7, Issue 2
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    Proteome-Based Systems Biology Analysis of the Diabetic Mouse Aorta Reveals Major Changes in Fatty Acid Biosynthesis as Potential Hallmark in Diabetes Mellitus–Associated Vascular DiseaseCLINICAL PERSPECTIVE
    Holger Husi, Tom Van Agtmael, William Mullen, Ferdinand H. Bahlmann, Joost P. Schanstra, Antonia Vlahou, Christian Delles, Paul Perco and Harald Mischak
    Circulation: Genomic and Precision Medicine. 2014;7:161-170, originally published February 26, 2014
    https://doi.org/10.1161/CIRCGENETICS.113.000196

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    Proteome-Based Systems Biology Analysis of the Diabetic Mouse Aorta Reveals Major Changes in Fatty Acid Biosynthesis as Potential Hallmark in Diabetes Mellitus–Associated Vascular DiseaseCLINICAL PERSPECTIVE
    Holger Husi, Tom Van Agtmael, William Mullen, Ferdinand H. Bahlmann, Joost P. Schanstra, Antonia Vlahou, Christian Delles, Paul Perco and Harald Mischak
    Circulation: Genomic and Precision Medicine. 2014;7:161-170, originally published February 26, 2014
    https://doi.org/10.1161/CIRCGENETICS.113.000196
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