Loss of TIMP3 exacerbates atherosclerosis in ApoE null mice

Atherosclerosis. 2014 Aug;235(2):438-43. doi: 10.1016/j.atherosclerosis.2014.05.946. Epub 2014 Jun 4.

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.

Keywords: Atherosclerosis; Inflammation; Metabolism; Metabolomics; TIMP3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency*
  • Atherosclerosis / genetics
  • Atherosclerosis / physiopathology*
  • Macrophages / pathology
  • Macrophages / physiology
  • Male
  • Metabolomics
  • Mice, Knockout
  • Plaque, Atherosclerotic / pathology
  • Tissue Inhibitor of Metalloproteinase-3 / deficiency*

Substances

  • Apolipoproteins E
  • Tissue Inhibitor of Metalloproteinase-3