title: 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 disease.
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.
  
  
  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.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK.
authors.forename: Holger
authors.initials: H
authors.lastname: Husi
authors.forename: Tom
authors.initials: T
authors.lastname: Van Agtmael
authors.forename: William
authors.initials: W
authors.lastname: Mullen
authors.forename: Ferdinand H
authors.initials: FH
authors.lastname: Bahlmann
authors.forename: Joost P
authors.initials: JP
authors.lastname: Schanstra
authors.forename: Antonia
authors.initials: A
authors.lastname: Vlahou
authors.forename: Christian
authors.initials: C
authors.lastname: Delles
authors.forename: Paul
authors.initials: P
authors.lastname: Perco
authors.forename: Harald
authors.initials: H
authors.lastname: Mischak
mesh_terms: D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D006801:Humans; D007657:Ketone Bodies / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D020543:Proteome; D040901:Proteomics; D049490:Systems Biology
chemical_list: D005227:Fatty Acids; D007657:Ketone Bodies; D020543:Proteome
keywords: aorta; blood supply; diabetes mellitus; ketone bodies; muscles; proteomics; smooth muscle; systems biology