Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques : Evidence for activation by proinflammatory mediators
Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques, where in their active form, they may contribute to vascular remodeling and plaque disruption. In this study, we tested the hypothesis that membrane type 1 MMP (MT1-MMP), a novel transmembrane MMP that activates pro-MMP-2 (gel...
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| Veröffentlicht in: | Circulation (New York, N.Y.) N.Y.), 1999-06, Vol.99 (24), p.3103-3109 |
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| creator | RAJAVASHISTH, T. B XU, X.-P SHAH, P. K JOVINGE, S MEISEL, S XU, X.-O CHAI, N.-N FISHBEIN, M. C KAUL, S CERCEK, B SHARIFI, B |
| description | Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques, where in their active form, they may contribute to vascular remodeling and plaque disruption. In this study, we tested the hypothesis that membrane type 1 MMP (MT1-MMP), a novel transmembrane MMP that activates pro-MMP-2 (gelatinase A), is expressed in human atherosclerotic plaques and that its expression is regulated by proinflammatory molecules.
MT1-MMP expression was examined in normal and atherosclerotic human arteries by immunocytochemistry with specific antibodies. MT1-MMP expression in human saphenous vein-derived smooth muscle cells (SMCs) maintained in tissue culture was determined under basal conditions and in response to proinflammatory molecules (interleukin [IL]-1alpha, tumor necrosis factor [TNF]-alpha, and oxidized LDL [ox-LDL]) by use of Northern blot and ribonuclease protection assays for mRNA, Western blot and immunoprecipitation for protein, and gelatin zymography for catalytic activity. Medial SMCs of normal vessel wall expressed MT1-MMP. In atherosclerotic arteries, MT1-MMP expression was noted within the complex atheroma colocalizing with SMCs and macrophages (Mphi). Cultured SMCs constitutively expressed MT1-MMP mRNA and protein, which increased 2- to 4-fold over control in a time-dependent manner within 4 to 8 hours of exposure to IL-1alpha, TNF-alpha, and ox-LDL (thiobarbituric acid-reactive substances, 13.4 nmol/mg LDL protein), whereas native LDL had no effect. Flow cytometry revealed MT1-MMP expression by human monocyte-derived Mphi, which increased 3.8-fold over baseline within 6 hours after exposure to 10 ng/mL TNF-alpha.
This study demonstrates that MT1-MMP, an activator of pro-MMP-2, is expressed by SMCs and Mphi in human atherosclerotic plaques. Furthermore, proinflammatory molecules upregulate MT1-MMP expression in vascular SMCs and Mphi. Thus, activation of SMCs and Mphi by proinflammatory molecules may influence extracellular matrix remodeling in atherosclerosis by regulating MT1-MMP expression. |
| doi_str_mv | 10.1161/01.CIR.99.24.3103 |
| format | Article |
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MT1-MMP expression was examined in normal and atherosclerotic human arteries by immunocytochemistry with specific antibodies. MT1-MMP expression in human saphenous vein-derived smooth muscle cells (SMCs) maintained in tissue culture was determined under basal conditions and in response to proinflammatory molecules (interleukin [IL]-1alpha, tumor necrosis factor [TNF]-alpha, and oxidized LDL [ox-LDL]) by use of Northern blot and ribonuclease protection assays for mRNA, Western blot and immunoprecipitation for protein, and gelatin zymography for catalytic activity. Medial SMCs of normal vessel wall expressed MT1-MMP. In atherosclerotic arteries, MT1-MMP expression was noted within the complex atheroma colocalizing with SMCs and macrophages (Mphi). Cultured SMCs constitutively expressed MT1-MMP mRNA and protein, which increased 2- to 4-fold over control in a time-dependent manner within 4 to 8 hours of exposure to IL-1alpha, TNF-alpha, and ox-LDL (thiobarbituric acid-reactive substances, 13.4 nmol/mg LDL protein), whereas native LDL had no effect. Flow cytometry revealed MT1-MMP expression by human monocyte-derived Mphi, which increased 3.8-fold over baseline within 6 hours after exposure to 10 ng/mL TNF-alpha.
This study demonstrates that MT1-MMP, an activator of pro-MMP-2, is expressed by SMCs and Mphi in human atherosclerotic plaques. Furthermore, proinflammatory molecules upregulate MT1-MMP expression in vascular SMCs and Mphi. Thus, activation of SMCs and Mphi by proinflammatory molecules may influence extracellular matrix remodeling in atherosclerosis by regulating MT1-MMP expression.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/01.CIR.99.24.3103</identifier><identifier>PMID: 10377072</identifier><identifier>CODEN: CIRCAZ</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Antibodies, Monoclonal ; Arteriosclerosis - metabolism ; Arteriosclerosis - pathology ; Atherosclerosis (general aspects, experimental research) ; Biological and medical sciences ; Blood and lymphatic vessels ; Blotting, Northern ; Cardiology. Vascular system ; Cells, Cultured ; Coronary Vessels - chemistry ; Coronary Vessels - enzymology ; Enzyme Precursors - metabolism ; Flow Cytometry ; Gelatinases - analysis ; Gelatinases - biosynthesis ; Gelatinases - immunology ; Gene Expression Regulation, Enzymologic - drug effects ; Gene Expression Regulation, Enzymologic - immunology ; Humans ; Inflammation Mediators - metabolism ; Interleukin-1 - pharmacology ; Lipoproteins - metabolism ; Lipoproteins, LDL - pharmacology ; Macrophages - chemistry ; Macrophages - enzymology ; Matrix Metalloproteinase 2 ; Matrix Metalloproteinases, Membrane-Associated ; Medical sciences ; Metalloendopeptidases - analysis ; Metalloendopeptidases - biosynthesis ; Metalloendopeptidases - genetics ; Metalloendopeptidases - immunology ; Metalloendopeptidases - metabolism ; Muscle, Smooth, Vascular - cytology ; Muscle, Smooth, Vascular - enzymology ; Muscle, Smooth, Vascular - pathology ; RNA, Messenger - analysis ; Saphenous Vein - cytology ; Tissue Inhibitor of Metalloproteinase-2 - analysis ; Tissue Inhibitor of Metalloproteinase-2 - immunology ; Tumor Necrosis Factor-alpha - pharmacology</subject><ispartof>Circulation (New York, N.Y.), 1999-06, Vol.99 (24), p.3103-3109</ispartof><rights>1999 INIST-CNRS</rights><rights>Copyright American Heart Association, Inc. Jun 22, 1999</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c279t-90ba7a79c9f5cb29e72adf354ea0aa0592e6b4893832e921d0f052e9bcb520a83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>310,311,315,781,785,790,791,3688,23935,23936,25145,27929,27930</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1848442$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10377072$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>RAJAVASHISTH, T. B</creatorcontrib><creatorcontrib>XU, X.-P</creatorcontrib><creatorcontrib>SHAH, P. K</creatorcontrib><creatorcontrib>JOVINGE, S</creatorcontrib><creatorcontrib>MEISEL, S</creatorcontrib><creatorcontrib>XU, X.-O</creatorcontrib><creatorcontrib>CHAI, N.-N</creatorcontrib><creatorcontrib>FISHBEIN, M. C</creatorcontrib><creatorcontrib>KAUL, S</creatorcontrib><creatorcontrib>CERCEK, B</creatorcontrib><creatorcontrib>SHARIFI, B</creatorcontrib><title>Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques : Evidence for activation by proinflammatory mediators</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques, where in their active form, they may contribute to vascular remodeling and plaque disruption. In this study, we tested the hypothesis that membrane type 1 MMP (MT1-MMP), a novel transmembrane MMP that activates pro-MMP-2 (gelatinase A), is expressed in human atherosclerotic plaques and that its expression is regulated by proinflammatory molecules.
MT1-MMP expression was examined in normal and atherosclerotic human arteries by immunocytochemistry with specific antibodies. MT1-MMP expression in human saphenous vein-derived smooth muscle cells (SMCs) maintained in tissue culture was determined under basal conditions and in response to proinflammatory molecules (interleukin [IL]-1alpha, tumor necrosis factor [TNF]-alpha, and oxidized LDL [ox-LDL]) by use of Northern blot and ribonuclease protection assays for mRNA, Western blot and immunoprecipitation for protein, and gelatin zymography for catalytic activity. Medial SMCs of normal vessel wall expressed MT1-MMP. In atherosclerotic arteries, MT1-MMP expression was noted within the complex atheroma colocalizing with SMCs and macrophages (Mphi). Cultured SMCs constitutively expressed MT1-MMP mRNA and protein, which increased 2- to 4-fold over control in a time-dependent manner within 4 to 8 hours of exposure to IL-1alpha, TNF-alpha, and ox-LDL (thiobarbituric acid-reactive substances, 13.4 nmol/mg LDL protein), whereas native LDL had no effect. Flow cytometry revealed MT1-MMP expression by human monocyte-derived Mphi, which increased 3.8-fold over baseline within 6 hours after exposure to 10 ng/mL TNF-alpha.
This study demonstrates that MT1-MMP, an activator of pro-MMP-2, is expressed by SMCs and Mphi in human atherosclerotic plaques. Furthermore, proinflammatory molecules upregulate MT1-MMP expression in vascular SMCs and Mphi. Thus, activation of SMCs and Mphi by proinflammatory molecules may influence extracellular matrix remodeling in atherosclerosis by regulating MT1-MMP expression.</description><subject>Antibodies, Monoclonal</subject><subject>Arteriosclerosis - metabolism</subject><subject>Arteriosclerosis - pathology</subject><subject>Atherosclerosis (general aspects, experimental research)</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Blotting, Northern</subject><subject>Cardiology. Vascular system</subject><subject>Cells, Cultured</subject><subject>Coronary Vessels - chemistry</subject><subject>Coronary Vessels - enzymology</subject><subject>Enzyme Precursors - metabolism</subject><subject>Flow Cytometry</subject><subject>Gelatinases - analysis</subject><subject>Gelatinases - biosynthesis</subject><subject>Gelatinases - immunology</subject><subject>Gene Expression Regulation, Enzymologic - drug effects</subject><subject>Gene Expression Regulation, Enzymologic - immunology</subject><subject>Humans</subject><subject>Inflammation Mediators - metabolism</subject><subject>Interleukin-1 - pharmacology</subject><subject>Lipoproteins - metabolism</subject><subject>Lipoproteins, LDL - pharmacology</subject><subject>Macrophages - chemistry</subject><subject>Macrophages - enzymology</subject><subject>Matrix Metalloproteinase 2</subject><subject>Matrix Metalloproteinases, Membrane-Associated</subject><subject>Medical sciences</subject><subject>Metalloendopeptidases - analysis</subject><subject>Metalloendopeptidases - biosynthesis</subject><subject>Metalloendopeptidases - genetics</subject><subject>Metalloendopeptidases - immunology</subject><subject>Metalloendopeptidases - metabolism</subject><subject>Muscle, Smooth, Vascular - cytology</subject><subject>Muscle, Smooth, Vascular - enzymology</subject><subject>Muscle, Smooth, Vascular - pathology</subject><subject>RNA, Messenger - analysis</subject><subject>Saphenous Vein - cytology</subject><subject>Tissue Inhibitor of Metalloproteinase-2 - analysis</subject><subject>Tissue Inhibitor of Metalloproteinase-2 - immunology</subject><subject>Tumor Necrosis Factor-alpha - pharmacology</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkd2KFDEQhYMo7rj6AN5IEPGu2_x0dzreLcOqCyuC6HWozlSzWfrPJL3sPIMvbTUzoHiTVOA7VSd1GHstRSllIz8IWe5vvpfWlqoqtRT6CdvJWlVFVWv7lO2EELYwWqkL9iKle3o22tTP2QWhxgijduz3Vxy7CBPyfFyQSz5CjuGRj5hhGOYlzhnDBAk5Pi4RUwrzxMPE79YRJg75DuOc_EBnDp4vA_xaMfGP_PohHHDyyPs5cvA5PEDepN2RU88w9QOMNGqORxp1CFuVXrJnPQwJX53vS_bz0_WP_Zfi9tvnm_3VbeGVsbmwogMDxnrb175TFo2CQ6_rCkEAiNoqbLqqtbrVCq2SB9GLmqrOd7US0OpL9v7Ul5xsdrMbQ_I4DLSGeU2usa0meUPg2__A-3mNE3lzSiqj21ooguQJ8rSJFLF3SwwjxKOTwm0xOSEdxeSsdapyW0ykeXNuvHb0_X8Up1wIeHcGIHkYekrIh_SXa6u2qpT-AwktnZw</recordid><startdate>19990622</startdate><enddate>19990622</enddate><creator>RAJAVASHISTH, T. B</creator><creator>XU, X.-P</creator><creator>SHAH, P. K</creator><creator>JOVINGE, S</creator><creator>MEISEL, S</creator><creator>XU, X.-O</creator><creator>CHAI, N.-N</creator><creator>FISHBEIN, M. C</creator><creator>KAUL, S</creator><creator>CERCEK, B</creator><creator>SHARIFI, B</creator><general>Lippincott Williams & Wilkins</general><general>American Heart Association, Inc</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>K9.</scope><scope>NAPCQ</scope><scope>U9A</scope><scope>7X8</scope></search><sort><creationdate>19990622</creationdate><title>Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques : Evidence for activation by proinflammatory mediators</title><author>RAJAVASHISTH, T. B ; XU, X.-P ; SHAH, P. K ; JOVINGE, S ; MEISEL, S ; XU, X.-O ; CHAI, N.-N ; FISHBEIN, M. C ; KAUL, S ; CERCEK, B ; SHARIFI, B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c279t-90ba7a79c9f5cb29e72adf354ea0aa0592e6b4893832e921d0f052e9bcb520a83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Antibodies, Monoclonal</topic><topic>Arteriosclerosis - metabolism</topic><topic>Arteriosclerosis - pathology</topic><topic>Atherosclerosis (general aspects, experimental research)</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Blotting, Northern</topic><topic>Cardiology. Vascular system</topic><topic>Cells, Cultured</topic><topic>Coronary Vessels - chemistry</topic><topic>Coronary Vessels - enzymology</topic><topic>Enzyme Precursors - metabolism</topic><topic>Flow Cytometry</topic><topic>Gelatinases - analysis</topic><topic>Gelatinases - biosynthesis</topic><topic>Gelatinases - immunology</topic><topic>Gene Expression Regulation, Enzymologic - drug effects</topic><topic>Gene Expression Regulation, Enzymologic - immunology</topic><topic>Humans</topic><topic>Inflammation Mediators - metabolism</topic><topic>Interleukin-1 - pharmacology</topic><topic>Lipoproteins - metabolism</topic><topic>Lipoproteins, LDL - pharmacology</topic><topic>Macrophages - chemistry</topic><topic>Macrophages - enzymology</topic><topic>Matrix Metalloproteinase 2</topic><topic>Matrix Metalloproteinases, Membrane-Associated</topic><topic>Medical sciences</topic><topic>Metalloendopeptidases - analysis</topic><topic>Metalloendopeptidases - biosynthesis</topic><topic>Metalloendopeptidases - genetics</topic><topic>Metalloendopeptidases - immunology</topic><topic>Metalloendopeptidases - metabolism</topic><topic>Muscle, Smooth, Vascular - cytology</topic><topic>Muscle, Smooth, Vascular - enzymology</topic><topic>Muscle, Smooth, Vascular - pathology</topic><topic>RNA, Messenger - analysis</topic><topic>Saphenous Vein - cytology</topic><topic>Tissue Inhibitor of Metalloproteinase-2 - analysis</topic><topic>Tissue Inhibitor of Metalloproteinase-2 - immunology</topic><topic>Tumor Necrosis Factor-alpha - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>RAJAVASHISTH, T. B</creatorcontrib><creatorcontrib>XU, X.-P</creatorcontrib><creatorcontrib>SHAH, P. K</creatorcontrib><creatorcontrib>JOVINGE, S</creatorcontrib><creatorcontrib>MEISEL, S</creatorcontrib><creatorcontrib>XU, X.-O</creatorcontrib><creatorcontrib>CHAI, N.-N</creatorcontrib><creatorcontrib>FISHBEIN, M. C</creatorcontrib><creatorcontrib>KAUL, S</creatorcontrib><creatorcontrib>CERCEK, B</creatorcontrib><creatorcontrib>SHARIFI, B</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>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>RAJAVASHISTH, T. B</au><au>XU, X.-P</au><au>SHAH, P. K</au><au>JOVINGE, S</au><au>MEISEL, S</au><au>XU, X.-O</au><au>CHAI, N.-N</au><au>FISHBEIN, M. C</au><au>KAUL, S</au><au>CERCEK, B</au><au>SHARIFI, B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques : Evidence for activation by proinflammatory mediators</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>1999-06-22</date><risdate>1999</risdate><volume>99</volume><issue>24</issue><spage>3103</spage><epage>3109</epage><pages>3103-3109</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><coden>CIRCAZ</coden><abstract>Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques, where in their active form, they may contribute to vascular remodeling and plaque disruption. In this study, we tested the hypothesis that membrane type 1 MMP (MT1-MMP), a novel transmembrane MMP that activates pro-MMP-2 (gelatinase A), is expressed in human atherosclerotic plaques and that its expression is regulated by proinflammatory molecules.
MT1-MMP expression was examined in normal and atherosclerotic human arteries by immunocytochemistry with specific antibodies. MT1-MMP expression in human saphenous vein-derived smooth muscle cells (SMCs) maintained in tissue culture was determined under basal conditions and in response to proinflammatory molecules (interleukin [IL]-1alpha, tumor necrosis factor [TNF]-alpha, and oxidized LDL [ox-LDL]) by use of Northern blot and ribonuclease protection assays for mRNA, Western blot and immunoprecipitation for protein, and gelatin zymography for catalytic activity. Medial SMCs of normal vessel wall expressed MT1-MMP. In atherosclerotic arteries, MT1-MMP expression was noted within the complex atheroma colocalizing with SMCs and macrophages (Mphi). Cultured SMCs constitutively expressed MT1-MMP mRNA and protein, which increased 2- to 4-fold over control in a time-dependent manner within 4 to 8 hours of exposure to IL-1alpha, TNF-alpha, and ox-LDL (thiobarbituric acid-reactive substances, 13.4 nmol/mg LDL protein), whereas native LDL had no effect. Flow cytometry revealed MT1-MMP expression by human monocyte-derived Mphi, which increased 3.8-fold over baseline within 6 hours after exposure to 10 ng/mL TNF-alpha.
This study demonstrates that MT1-MMP, an activator of pro-MMP-2, is expressed by SMCs and Mphi in human atherosclerotic plaques. Furthermore, proinflammatory molecules upregulate MT1-MMP expression in vascular SMCs and Mphi. Thus, activation of SMCs and Mphi by proinflammatory molecules may influence extracellular matrix remodeling in atherosclerosis by regulating MT1-MMP expression.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>10377072</pmid><doi>10.1161/01.CIR.99.24.3103</doi><tpages>7</tpages></addata></record> |
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| ispartof | Circulation (New York, N.Y.), 1999-06, Vol.99 (24), p.3103-3109 |
| issn | 0009-7322 1524-4539 |
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| source | MEDLINE; American Heart Association Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Journals@Ovid Complete |
| subjects | Antibodies, Monoclonal Arteriosclerosis - metabolism Arteriosclerosis - pathology Atherosclerosis (general aspects, experimental research) Biological and medical sciences Blood and lymphatic vessels Blotting, Northern Cardiology. Vascular system Cells, Cultured Coronary Vessels - chemistry Coronary Vessels - enzymology Enzyme Precursors - metabolism Flow Cytometry Gelatinases - analysis Gelatinases - biosynthesis Gelatinases - immunology Gene Expression Regulation, Enzymologic - drug effects Gene Expression Regulation, Enzymologic - immunology Humans Inflammation Mediators - metabolism Interleukin-1 - pharmacology Lipoproteins - metabolism Lipoproteins, LDL - pharmacology Macrophages - chemistry Macrophages - enzymology Matrix Metalloproteinase 2 Matrix Metalloproteinases, Membrane-Associated Medical sciences Metalloendopeptidases - analysis Metalloendopeptidases - biosynthesis Metalloendopeptidases - genetics Metalloendopeptidases - immunology Metalloendopeptidases - metabolism Muscle, Smooth, Vascular - cytology Muscle, Smooth, Vascular - enzymology Muscle, Smooth, Vascular - pathology RNA, Messenger - analysis Saphenous Vein - cytology Tissue Inhibitor of Metalloproteinase-2 - analysis Tissue Inhibitor of Metalloproteinase-2 - immunology Tumor Necrosis Factor-alpha - pharmacology |
| title | Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques : Evidence for activation by proinflammatory mediators |
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