title: Loss of TIMP3 exacerbates atherosclerosis in ApoE null mice.
abstract: BACKGROUND
  Tissue inhibitor of metalloproteinase 3 (TIMP3) is a stromal protein that inhibits the activity of various proteases and receptors. We have previously shown TIMP3 to be downregulated in metabolic and inflammatory disorders, such as type 2 diabetes mellitus. We have now generated an ApoE(-/-)Timp3(-/-) mouse model in which, through the use of genetics, metabolomics and in-vivo phenotypical analysis we investigated the role of TIMP3 in the development of atherosclerosis.
  
  
  RESULTS
  En face aorta analysis and aortic root examination showed that ApoE(-/-)Timp3(-/-) mice show increased atherosclerosis with increased infiltration of macrophages into the plaque. Serum concentration of MCP-1 were elevated in the serum of ApoE(-/-)Timp3(-/-) mice coupled with an expansion of the inflammatory (M1) Gr1+ macrophages, both in the circulation and within the aortic tissue. Targeted analysis of metabolites revealed a trend to reduced short chain acylcarnitines.
  
  
  CONCLUSIONS
  Our study shows that lack of TIMP3 increases inflammation and polarizes macrophages towards a more inflammatory phenotype resulting in increased atherosclerosis.
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Robert
authors.initials: R
authors.lastname: Stöhr
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cavalera
authors.affiliation: Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Menini
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Mavilio
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Casagrande
authors.affiliation: Center of Excellence on Aging (Ce.S.I.), University Foundation, Chieti, Italy; Department of Clinical and Experimental Sciences, G. D'Annunzio University, Chieti, Pescara, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Rossi
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy; Fondazione Santa Lucia-IRCCS, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Urbani
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; Center for Atherosclerosis, Department of Medicine, Policlinico Tor Vergata, 00133 Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Cardellini
authors.affiliation: Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pugliese
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Menghini
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; Center for Atherosclerosis, Department of Medicine, Policlinico Tor Vergata, 00133 Rome, Italy. Electronic address: federicm@uniroma2.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000235:genetics / Q000503:physiopathology*; D008264:Macrophages / Q000473:pathology / Q000502:physiology; D008297:Male; D055432:Metabolomics; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000473:pathology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency*
chemical_list: D001057:Apolipoproteins E; D019717:Tissue Inhibitor of Metalloproteinase-3
keywords: Atherosclerosis; Inflammation; Metabolism; Metabolomics; TIMP3