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
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. 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. Our study shows that lack of TIMP3 increases inflammation and polarizes macrophages towards a more inflammatory phenotype resulting in increased atherosclerosis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Loss of TIMP3 exacerbates atherosclerosis in ApoE null mice / Robert, S., Michele, C., Menini, S., Maria, M., Viviana, C., Claudia, R., Andrea, U., Marina, C., Pugliese, G., Rossella, M., Massimo, F.. - In: ATHEROSCLEROSIS. - ISSN 0021-9150. - 235:2(2014), pp. 438-443. [10.1016/j.atherosclerosis.2014.05.946]
Loss of TIMP3 exacerbates atherosclerosis in ApoE null mice.
MENINI, Stefano;PUGLIESE, Giuseppe;
2014
Abstract
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 ofI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
