Loss of TIMP3 exacerbates atherosclerosis in ApoE null mice

Robert Stöhr, Michele Cavalera, Stefano Menini, Maria Mavilio, Viviana Casagrande, Claudia Rossi, Andrea Urbani, Marina Cardellini, Giuseppe Pugliese, Rossella Menghini, Massimo Federici

Research output: Contribution to journalArticle

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. Methods and 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.

Original languageEnglish
Pages (from-to)438-443
Number of pages6
JournalAtherosclerosis
Volume235
Issue number2
DOIs
Publication statusPublished - Aug 1 2014

Keywords

  • Atherosclerosis
  • Inflammation
  • Metabolism
  • Metabolomics
  • TIMP3

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

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    Stöhr, R., Cavalera, M., Menini, S., Mavilio, M., Casagrande, V., Rossi, C., Urbani, A., Cardellini, M., Pugliese, G., Menghini, R., & Federici, M. (2014). Loss of TIMP3 exacerbates atherosclerosis in ApoE null mice. Atherosclerosis, 235(2), 438-443. https://doi.org/10.1016/j.atherosclerosis.2014.05.946