Overexpression of Tissue Inhibitor of Metalloproteinase 3 in Macrophages Reduces Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice
OBJECTIVE—Tissue inhibitor of metalloproteinase 3 (TIMP3) is a stromal protein that inhibits the activity of proteases and receptors. TIMP3 is downregulated in metabolic and inflammatory disorders, such as type 2 diabetes mellitus and atherosclerosis, particularly in regions enriched with monocyte/m...
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| Veröffentlicht in: | Arteriosclerosis, thrombosis, and vascular biology thrombosis, and vascular biology, 2012-01, Vol.32 (1), p.74-81 |
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| creator | Casagrande, Viviana Menghini, Rossella Menini, Stefano Marino, Arianna Marchetti, Valentina Cavalera, Michele Fabrizi, Marta Hribal, Marta L Pugliese, Giuseppe Gentileschi, Paolo Schillaci, Orazio Porzio, Ottavia Lauro, Davide Sbraccia, Paolo Lauro, Renato Federici, Massimo |
| description | OBJECTIVE—Tissue inhibitor of metalloproteinase 3 (TIMP3) is a stromal protein that inhibits the activity of proteases and receptors. TIMP3 is downregulated in metabolic and inflammatory disorders, such as type 2 diabetes mellitus and atherosclerosis, particularly in regions enriched with monocyte/macrophage cells. To investigate the role of TIMP3 in atherosclerosis, we generated a new mouse model in which Timp3 was overexpressed in the atherosclerotic plaque via a macrophage-specific promoter (MacT3). We elucidated any potential antiatherosclerotic effects of TIMP3, including regulation of monocyte/macrophage recruitment within atherosclerotic plaques, in MacT3 mice crossbred with low-density lipoprotein receptor knockout (LDLR) mice.
METHODS AND RESULTS—MacT3/LDLR mice had an improvement of atherosclerosis and metabolic parameters compared with LDLR. En face aorta and aortic root examination of MacT3/LDLR mice revealed smaller atherosclerotic plaques with features of stability, such as increased collagen content and decreased necrotic core formation. Atherosclerotic plaques in MacT3/LDLR mice contained fewer T cells and macrophages. Furthermore, TIMP3 overexpression in macrophages resulted in reduced oxidative stress signals, as evidenced by lower lipid peroxidation, protein carbonylation, and nitration in atheromas.
CONCLUSION—Our study confirmed that macrophage-specific overexpression of TIMP3 decreases the inflammatory content and the amplitude of atherosclerotic plaques in mice. |
| doi_str_mv | 10.1161/ATVBAHA.111.238402 |
| format | Article |
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METHODS AND RESULTS—MacT3/LDLR mice had an improvement of atherosclerosis and metabolic parameters compared with LDLR. En face aorta and aortic root examination of MacT3/LDLR mice revealed smaller atherosclerotic plaques with features of stability, such as increased collagen content and decreased necrotic core formation. Atherosclerotic plaques in MacT3/LDLR mice contained fewer T cells and macrophages. Furthermore, TIMP3 overexpression in macrophages resulted in reduced oxidative stress signals, as evidenced by lower lipid peroxidation, protein carbonylation, and nitration in atheromas.
CONCLUSION—Our study confirmed that macrophage-specific overexpression of TIMP3 decreases the inflammatory content and the amplitude of atherosclerotic plaques in mice.</description><identifier>ISSN: 1079-5642</identifier><identifier>EISSN: 1524-4636</identifier><identifier>DOI: 10.1161/ATVBAHA.111.238402</identifier><identifier>PMID: 22015660</identifier><identifier>CODEN: ATVBFA</identifier><language>eng</language><publisher>Philadelphia, PA: American Heart Association, Inc</publisher><subject>Animals ; Atherosclerosis (general aspects, experimental research) ; Atherosclerosis - genetics ; Atherosclerosis - metabolism ; Atherosclerosis - pathology ; Atherosclerosis - prevention & control ; Biological and medical sciences ; Blood and lymphatic vessels ; Blood. Blood coagulation. Reticuloendothelial system ; Cardiology. Vascular system ; Diet, Atherogenic - adverse effects ; Disease Models, Animal ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Macrophages - metabolism ; Male ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Pharmacology. Drug treatments ; Promoter Regions, Genetic ; Receptors, LDL - deficiency ; Receptors, LDL - genetics ; Tissue Inhibitor of Metalloproteinase-3 - genetics ; Tissue Inhibitor of Metalloproteinase-3 - metabolism ; Up-Regulation</subject><ispartof>Arteriosclerosis, thrombosis, and vascular biology, 2012-01, Vol.32 (1), p.74-81</ispartof><rights>2012 American Heart Association, Inc.</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4870-b52560c7387cbe2dceae60557229b424ea4d3d80b4e1289431408f953ea805163</citedby><cites>FETCH-LOGICAL-c4870-b52560c7387cbe2dceae60557229b424ea4d3d80b4e1289431408f953ea805163</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,4010,27904,27905,27906</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25489154$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22015660$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Casagrande, Viviana</creatorcontrib><creatorcontrib>Menghini, Rossella</creatorcontrib><creatorcontrib>Menini, Stefano</creatorcontrib><creatorcontrib>Marino, Arianna</creatorcontrib><creatorcontrib>Marchetti, Valentina</creatorcontrib><creatorcontrib>Cavalera, Michele</creatorcontrib><creatorcontrib>Fabrizi, Marta</creatorcontrib><creatorcontrib>Hribal, Marta L</creatorcontrib><creatorcontrib>Pugliese, Giuseppe</creatorcontrib><creatorcontrib>Gentileschi, Paolo</creatorcontrib><creatorcontrib>Schillaci, Orazio</creatorcontrib><creatorcontrib>Porzio, Ottavia</creatorcontrib><creatorcontrib>Lauro, Davide</creatorcontrib><creatorcontrib>Sbraccia, Paolo</creatorcontrib><creatorcontrib>Lauro, Renato</creatorcontrib><creatorcontrib>Federici, Massimo</creatorcontrib><title>Overexpression of Tissue Inhibitor of Metalloproteinase 3 in Macrophages Reduces Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice</title><title>Arteriosclerosis, thrombosis, and vascular biology</title><addtitle>Arterioscler Thromb Vasc Biol</addtitle><description>OBJECTIVE—Tissue inhibitor of metalloproteinase 3 (TIMP3) is a stromal protein that inhibits the activity of proteases and receptors. TIMP3 is downregulated in metabolic and inflammatory disorders, such as type 2 diabetes mellitus and atherosclerosis, particularly in regions enriched with monocyte/macrophage cells. To investigate the role of TIMP3 in atherosclerosis, we generated a new mouse model in which Timp3 was overexpressed in the atherosclerotic plaque via a macrophage-specific promoter (MacT3). We elucidated any potential antiatherosclerotic effects of TIMP3, including regulation of monocyte/macrophage recruitment within atherosclerotic plaques, in MacT3 mice crossbred with low-density lipoprotein receptor knockout (LDLR) mice.
METHODS AND RESULTS—MacT3/LDLR mice had an improvement of atherosclerosis and metabolic parameters compared with LDLR. En face aorta and aortic root examination of MacT3/LDLR mice revealed smaller atherosclerotic plaques with features of stability, such as increased collagen content and decreased necrotic core formation. Atherosclerotic plaques in MacT3/LDLR mice contained fewer T cells and macrophages. Furthermore, TIMP3 overexpression in macrophages resulted in reduced oxidative stress signals, as evidenced by lower lipid peroxidation, protein carbonylation, and nitration in atheromas.
CONCLUSION—Our study confirmed that macrophage-specific overexpression of TIMP3 decreases the inflammatory content and the amplitude of atherosclerotic plaques in mice.</description><subject>Animals</subject><subject>Atherosclerosis (general aspects, experimental research)</subject><subject>Atherosclerosis - genetics</subject><subject>Atherosclerosis - metabolism</subject><subject>Atherosclerosis - pathology</subject><subject>Atherosclerosis - prevention & control</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Blood. Blood coagulation. Reticuloendothelial system</subject><subject>Cardiology. Vascular system</subject><subject>Diet, Atherogenic - adverse effects</subject><subject>Disease Models, Animal</subject><subject>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</subject><subject>Macrophages - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Pharmacology. Drug treatments</subject><subject>Promoter Regions, Genetic</subject><subject>Receptors, LDL - deficiency</subject><subject>Receptors, LDL - genetics</subject><subject>Tissue Inhibitor of Metalloproteinase-3 - genetics</subject><subject>Tissue Inhibitor of Metalloproteinase-3 - metabolism</subject><subject>Up-Regulation</subject><issn>1079-5642</issn><issn>1524-4636</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkdtu1DAQhiMEoqXwAlyg3CCuUnzM4TKUQyt2VQkt3FqOMyGm3jh4HJa-Bk-Mo92CZHs81je_Pf6z7CUll5SW9G27-_auvW5TQi8ZrwVhj7JzKpkoRMnLx2lPqqaQpWBn2TPEH4QQwRh5mp2llcqyJOfZn9tfEOD3HADR-in3Q76ziAvkN9NoOxt9WM-2ELVzfg4-gp00Qs5zO-VbbYKfR_0dMP8C_WJSbOMIwaNx62pxxTb-ULyHCW28zzd2fpBJJQbm9YbPkzd3fon51hp4nj0ZtEN4cYoX2dePH3ZX18Xm9tPNVbspjKgrUnSSyZKYiteV6YD1BjSURMqKsaYTTIAWPe9r0gmgrG4Ep4LUQyM56JpIWvKL7M1RNz3n5wIY1d6iAef0BH5B1VDaSMIakkh2JFO3iAEGNQe71-FeUaJWK9TJipRQdbQiFb06yS_dHvp_JQ9_n4DXJ0Cj0W4IejIW_3NS1A2VInHiyB28ixDwzi0HCGoE7eKoVlN56rtIsmmktEiTEv4XxFWjIg</recordid><startdate>201201</startdate><enddate>201201</enddate><creator>Casagrande, Viviana</creator><creator>Menghini, Rossella</creator><creator>Menini, Stefano</creator><creator>Marino, Arianna</creator><creator>Marchetti, Valentina</creator><creator>Cavalera, Michele</creator><creator>Fabrizi, Marta</creator><creator>Hribal, Marta L</creator><creator>Pugliese, Giuseppe</creator><creator>Gentileschi, Paolo</creator><creator>Schillaci, Orazio</creator><creator>Porzio, Ottavia</creator><creator>Lauro, Davide</creator><creator>Sbraccia, Paolo</creator><creator>Lauro, Renato</creator><creator>Federici, Massimo</creator><general>American Heart Association, Inc</general><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201201</creationdate><title>Overexpression of Tissue Inhibitor of Metalloproteinase 3 in Macrophages Reduces Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice</title><author>Casagrande, Viviana ; Menghini, Rossella ; Menini, Stefano ; Marino, Arianna ; Marchetti, Valentina ; Cavalera, Michele ; Fabrizi, Marta ; Hribal, Marta L ; Pugliese, Giuseppe ; Gentileschi, Paolo ; Schillaci, Orazio ; Porzio, Ottavia ; Lauro, Davide ; Sbraccia, Paolo ; Lauro, Renato ; Federici, Massimo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4870-b52560c7387cbe2dceae60557229b424ea4d3d80b4e1289431408f953ea805163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Atherosclerosis (general aspects, experimental research)</topic><topic>Atherosclerosis - genetics</topic><topic>Atherosclerosis - metabolism</topic><topic>Atherosclerosis - pathology</topic><topic>Atherosclerosis - prevention & control</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Blood. Blood coagulation. Reticuloendothelial system</topic><topic>Cardiology. Vascular system</topic><topic>Diet, Atherogenic - adverse effects</topic><topic>Disease Models, Animal</topic><topic>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</topic><topic>Macrophages - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Pharmacology. Drug treatments</topic><topic>Promoter Regions, Genetic</topic><topic>Receptors, LDL - deficiency</topic><topic>Receptors, LDL - genetics</topic><topic>Tissue Inhibitor of Metalloproteinase-3 - genetics</topic><topic>Tissue Inhibitor of Metalloproteinase-3 - metabolism</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Casagrande, Viviana</creatorcontrib><creatorcontrib>Menghini, Rossella</creatorcontrib><creatorcontrib>Menini, Stefano</creatorcontrib><creatorcontrib>Marino, Arianna</creatorcontrib><creatorcontrib>Marchetti, Valentina</creatorcontrib><creatorcontrib>Cavalera, Michele</creatorcontrib><creatorcontrib>Fabrizi, Marta</creatorcontrib><creatorcontrib>Hribal, Marta L</creatorcontrib><creatorcontrib>Pugliese, Giuseppe</creatorcontrib><creatorcontrib>Gentileschi, Paolo</creatorcontrib><creatorcontrib>Schillaci, Orazio</creatorcontrib><creatorcontrib>Porzio, Ottavia</creatorcontrib><creatorcontrib>Lauro, Davide</creatorcontrib><creatorcontrib>Sbraccia, Paolo</creatorcontrib><creatorcontrib>Lauro, Renato</creatorcontrib><creatorcontrib>Federici, Massimo</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Casagrande, Viviana</au><au>Menghini, Rossella</au><au>Menini, Stefano</au><au>Marino, Arianna</au><au>Marchetti, Valentina</au><au>Cavalera, Michele</au><au>Fabrizi, Marta</au><au>Hribal, Marta L</au><au>Pugliese, Giuseppe</au><au>Gentileschi, Paolo</au><au>Schillaci, Orazio</au><au>Porzio, Ottavia</au><au>Lauro, Davide</au><au>Sbraccia, Paolo</au><au>Lauro, Renato</au><au>Federici, Massimo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Overexpression of Tissue Inhibitor of Metalloproteinase 3 in Macrophages Reduces Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice</atitle><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle><addtitle>Arterioscler Thromb Vasc Biol</addtitle><date>2012-01</date><risdate>2012</risdate><volume>32</volume><issue>1</issue><spage>74</spage><epage>81</epage><pages>74-81</pages><issn>1079-5642</issn><eissn>1524-4636</eissn><coden>ATVBFA</coden><abstract>OBJECTIVE—Tissue inhibitor of metalloproteinase 3 (TIMP3) is a stromal protein that inhibits the activity of proteases and receptors. TIMP3 is downregulated in metabolic and inflammatory disorders, such as type 2 diabetes mellitus and atherosclerosis, particularly in regions enriched with monocyte/macrophage cells. To investigate the role of TIMP3 in atherosclerosis, we generated a new mouse model in which Timp3 was overexpressed in the atherosclerotic plaque via a macrophage-specific promoter (MacT3). We elucidated any potential antiatherosclerotic effects of TIMP3, including regulation of monocyte/macrophage recruitment within atherosclerotic plaques, in MacT3 mice crossbred with low-density lipoprotein receptor knockout (LDLR) mice.
METHODS AND RESULTS—MacT3/LDLR mice had an improvement of atherosclerosis and metabolic parameters compared with LDLR. En face aorta and aortic root examination of MacT3/LDLR mice revealed smaller atherosclerotic plaques with features of stability, such as increased collagen content and decreased necrotic core formation. Atherosclerotic plaques in MacT3/LDLR mice contained fewer T cells and macrophages. Furthermore, TIMP3 overexpression in macrophages resulted in reduced oxidative stress signals, as evidenced by lower lipid peroxidation, protein carbonylation, and nitration in atheromas.
CONCLUSION—Our study confirmed that macrophage-specific overexpression of TIMP3 decreases the inflammatory content and the amplitude of atherosclerotic plaques in mice.</abstract><cop>Philadelphia, PA</cop><pub>American Heart Association, Inc</pub><pmid>22015660</pmid><doi>10.1161/ATVBAHA.111.238402</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Arteriosclerosis, thrombosis, and vascular biology, 2012-01, Vol.32 (1), p.74-81 |
| issn | 1079-5642 1524-4636 |
| language | eng |
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| source | MEDLINE; Journals@Ovid Complete; Alma/SFX Local Collection |
| subjects | Animals Atherosclerosis (general aspects, experimental research) Atherosclerosis - genetics Atherosclerosis - metabolism Atherosclerosis - pathology Atherosclerosis - prevention & control Biological and medical sciences Blood and lymphatic vessels Blood. Blood coagulation. Reticuloendothelial system Cardiology. Vascular system Diet, Atherogenic - adverse effects Disease Models, Animal Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Macrophages - metabolism Male Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Pharmacology. Drug treatments Promoter Regions, Genetic Receptors, LDL - deficiency Receptors, LDL - genetics Tissue Inhibitor of Metalloproteinase-3 - genetics Tissue Inhibitor of Metalloproteinase-3 - metabolism Up-Regulation |
| title | Overexpression of Tissue Inhibitor of Metalloproteinase 3 in Macrophages Reduces Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice |
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