Robert Stöhr1, Michele Cavalera1, Stefano Menini2, Maria Mavilio1, Viviana Casagrande1, Claudia Rossi3, Andrea Urbani4, Marina Cardellini5, Giuseppe Pugliese2, Rossella Menghini1, Massimo Federici6. 1. Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy. 2. Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy. 3. Center of Excellence on Aging (Ce.S.I.), University Foundation, Chieti, Italy; Department of Clinical and Experimental Sciences, G. D'Annunzio University, Chieti, Pescara, Italy. 4. Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy; Fondazione Santa Lucia-IRCCS, Rome, Italy. 5. Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; Center for Atherosclerosis, Department of Medicine, Policlinico Tor Vergata, 00133 Rome, Italy. 6. Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; Center for Atherosclerosis, Department of Medicine, Policlinico Tor Vergata, 00133 Rome, Italy. Electronic address: federicm@uniroma2.it.
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.
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 TIMP3increases inflammation and polarizes macrophages towards a more inflammatory phenotype resulting in increased atherosclerosis.
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