Journal
ATHEROSCLEROSIS
Volume 235, Issue 2, Pages 438-443Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2014.05.946
Keywords
Atherosclerosis; TIMP3; Metabolomics; Inflammation; Metabolism
Funding
- Fondazione Roma Grant
- Progetto SID
- FP-7 EURHYTHDIA [278397]
- FP7-FLORINASH [Health-F2-2009-241913]
- PRIN [20123BJ89E]
- Associazione Italiana per la Ricerca sul Cancro [AIRC IG-13163]
- Deutsche Herzstiftung (DHS)
- University of Rome Tor Vergata
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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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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