Loss of TIMP3 exacerbates atherosclerosis in ApoE null mice

Background:Tissue inhibitor of metalloproteinase 3 (TIMP3) is a stromal protein that inhibits the activityof various proteases and receptors. We have previously shown TIMP3 to be downregulated in metabolicand 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 ofatherosclerosis.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. Serumconcentration of MCP-1 were elevated in the serum of ApoE/Timp3/mice coupled with an expan-sion of the inflammatory (M1) Gr1þmacrophages, 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 macrophagestowards a more inflammatory phenotype resulting in increased atherosclerosis