Loss of TIMP3 exacerbates atherosclerosis in ApoE null mice

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.