Inhibition of MDM2 attenuates neointimal hyperplasia via suppression of vascular proliferation and inflammation
Tumour protein p53 plays an important role in the vascular remodelling process as well as in oncogenesis. p53 is negatively regulated by murine double minute 2 (MDM2). A recently developed MDM2 inhibitor, nutlin-3, is a non-genotoxic activator of the p53 pathway. So far, the effect of MDM2 inhibitio...
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| Veröffentlicht in: | Cardiovascular research 2011-09, Vol.91 (4), p.711-719 |
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| creator | HASHIMOTO, Toru ICHIKI, Toshihiro IKEDA, Jiro NARABAYASHI, Eriko MATSUURA, Hirohide MIYAZAKI, Ryohei INANAGA, Keita TAKEDA, Kotaro SUNAGAWA, Kenji |
| description | Tumour protein p53 plays an important role in the vascular remodelling process as well as in oncogenesis. p53 is negatively regulated by murine double minute 2 (MDM2). A recently developed MDM2 inhibitor, nutlin-3, is a non-genotoxic activator of the p53 pathway. So far, the effect of MDM2 inhibition on vascular remodelling has not been elucidated. We therefore investigated the effect of nutlin-3 on neointima formation.
Nutlin-3 up-regulated p53 and its downstream target p21 in vascular smooth muscle cells (VSMCs). DNA synthesis assay and flow cytometric analysis revealed that nutlin-3 inhibited platelet-derived growth factor (PDGF)-induced VSMC proliferation by cell cycle arrest. This inhibitory effect was abrogated in p53-siRNA-transfected VSMCs. Furthermore, nutlin-3 inhibited PDGF-stimulated VSMC migration. Treatment with nutlin-3 attenuated neointimal hyperplasia at 28 days after vascular injury in mice, associated with up-regulation of p53 and p21. BrdU incorporation was decreased at 14 days after injury in nutlin-3-treated mice. TUNEL assay showed that nutlin-3 did not exaggerate apoptosis of the injured vessels. Infiltration of macrophages and T-lymphocytes and mRNA expression of chemokine (C-C motif) ligand-5, interleukin-6, and intercellular adhesion molecule-1 were decreased in the injured vessels of nutlin-3-treated mice. Nutlin-3 suppressed NF-κB activation in VSMCs, but not in p53-siRNA-transfected VSMCs.
The MDM2 antagonist nutlin-3 inhibits VSMC proliferation, migration, and NF-κB activation, and also attenuates neointimal hyperplasia after vascular injury in mice, which is associated with suppression of vascular cell proliferation and an inflammatory response. Targeting MDM2 might be a potential therapeutic strategy for the treatment of vascular proliferative diseases. |
| doi_str_mv | 10.1093/cvr/cvr108 |
| format | Article |
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Nutlin-3 up-regulated p53 and its downstream target p21 in vascular smooth muscle cells (VSMCs). DNA synthesis assay and flow cytometric analysis revealed that nutlin-3 inhibited platelet-derived growth factor (PDGF)-induced VSMC proliferation by cell cycle arrest. This inhibitory effect was abrogated in p53-siRNA-transfected VSMCs. Furthermore, nutlin-3 inhibited PDGF-stimulated VSMC migration. Treatment with nutlin-3 attenuated neointimal hyperplasia at 28 days after vascular injury in mice, associated with up-regulation of p53 and p21. BrdU incorporation was decreased at 14 days after injury in nutlin-3-treated mice. TUNEL assay showed that nutlin-3 did not exaggerate apoptosis of the injured vessels. Infiltration of macrophages and T-lymphocytes and mRNA expression of chemokine (C-C motif) ligand-5, interleukin-6, and intercellular adhesion molecule-1 were decreased in the injured vessels of nutlin-3-treated mice. Nutlin-3 suppressed NF-κB activation in VSMCs, but not in p53-siRNA-transfected VSMCs.
The MDM2 antagonist nutlin-3 inhibits VSMC proliferation, migration, and NF-κB activation, and also attenuates neointimal hyperplasia after vascular injury in mice, which is associated with suppression of vascular cell proliferation and an inflammatory response. Targeting MDM2 might be a potential therapeutic strategy for the treatment of vascular proliferative diseases.</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1093/cvr/cvr108</identifier><identifier>PMID: 21498419</identifier><identifier>CODEN: CVREAU</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Animals ; Biological and medical sciences ; Cardiology. Vascular system ; Cell Cycle - drug effects ; Cell Movement - drug effects ; Cell Proliferation - drug effects ; Hyperplasia ; Imidazoles - pharmacology ; Inflammation - prevention & control ; Male ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Muscle, Smooth, Vascular - cytology ; Neointima - pathology ; NF-kappa B - metabolism ; Piperazines - pharmacology ; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2 - physiology ; Rats ; Rats, Sprague-Dawley ; Tumor Suppressor Protein p53 - physiology</subject><ispartof>Cardiovascular research, 2011-09, Vol.91 (4), p.711-719</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-d70ce214125105f493ce5efa854fab48b5ca7f10f0aa87aaab5f7de36eb710e13</citedby><cites>FETCH-LOGICAL-c418t-d70ce214125105f493ce5efa854fab48b5ca7f10f0aa87aaab5f7de36eb710e13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24436691$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21498419$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>HASHIMOTO, Toru</creatorcontrib><creatorcontrib>ICHIKI, Toshihiro</creatorcontrib><creatorcontrib>IKEDA, Jiro</creatorcontrib><creatorcontrib>NARABAYASHI, Eriko</creatorcontrib><creatorcontrib>MATSUURA, Hirohide</creatorcontrib><creatorcontrib>MIYAZAKI, Ryohei</creatorcontrib><creatorcontrib>INANAGA, Keita</creatorcontrib><creatorcontrib>TAKEDA, Kotaro</creatorcontrib><creatorcontrib>SUNAGAWA, Kenji</creatorcontrib><title>Inhibition of MDM2 attenuates neointimal hyperplasia via suppression of vascular proliferation and inflammation</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>Tumour protein p53 plays an important role in the vascular remodelling process as well as in oncogenesis. p53 is negatively regulated by murine double minute 2 (MDM2). A recently developed MDM2 inhibitor, nutlin-3, is a non-genotoxic activator of the p53 pathway. So far, the effect of MDM2 inhibition on vascular remodelling has not been elucidated. We therefore investigated the effect of nutlin-3 on neointima formation.
Nutlin-3 up-regulated p53 and its downstream target p21 in vascular smooth muscle cells (VSMCs). DNA synthesis assay and flow cytometric analysis revealed that nutlin-3 inhibited platelet-derived growth factor (PDGF)-induced VSMC proliferation by cell cycle arrest. This inhibitory effect was abrogated in p53-siRNA-transfected VSMCs. Furthermore, nutlin-3 inhibited PDGF-stimulated VSMC migration. Treatment with nutlin-3 attenuated neointimal hyperplasia at 28 days after vascular injury in mice, associated with up-regulation of p53 and p21. BrdU incorporation was decreased at 14 days after injury in nutlin-3-treated mice. TUNEL assay showed that nutlin-3 did not exaggerate apoptosis of the injured vessels. Infiltration of macrophages and T-lymphocytes and mRNA expression of chemokine (C-C motif) ligand-5, interleukin-6, and intercellular adhesion molecule-1 were decreased in the injured vessels of nutlin-3-treated mice. Nutlin-3 suppressed NF-κB activation in VSMCs, but not in p53-siRNA-transfected VSMCs.
The MDM2 antagonist nutlin-3 inhibits VSMC proliferation, migration, and NF-κB activation, and also attenuates neointimal hyperplasia after vascular injury in mice, which is associated with suppression of vascular cell proliferation and an inflammatory response. Targeting MDM2 might be a potential therapeutic strategy for the treatment of vascular proliferative diseases.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cardiology. Vascular system</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Movement - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Hyperplasia</subject><subject>Imidazoles - pharmacology</subject><subject>Inflammation - prevention & control</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Muscle, Smooth, Vascular - cytology</subject><subject>Neointima - pathology</subject><subject>NF-kappa B - metabolism</subject><subject>Piperazines - pharmacology</subject><subject>Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-mdm2 - physiology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Tumor Suppressor Protein p53 - physiology</subject><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1LxDAQhoMouq5e_AHSiwhCNWmSNj3K-gkrXvRcpumEjaQfJu2C_964u-phCBOeeZl5CDlj9JrRkt_otf8pRtUembFCypRnQu6TGaVUpTnP-RE5DuEjtlIW4pAcZUyUSrByRvrnbmVrO9q-S3qTvNy9ZAmMI3YTjBiSDnvbjbYFl6y-BvSDg2AhWccK0zB4DGE3uYagJwc-GXzvrEEPm0zomsR2xkHbbj5OyIEBF_B0987J-8P92-IpXb4-Pi9ul6kWTI1pU1CNcUuWSUalESXXKNGAksJALVQtNRSGUUMBVAEAtTRFgzzHumAUGZ-Ty21uXOdzwjBWrQ0anYN40hQqpURWRB0ykldbUvs-BI-mGnw82H9VjFY_fqvottr6jfD5LnaqW2z-0F-hEbjYAdEHOOOh0zb8c0LwPC8Z_wZYd4dW</recordid><startdate>20110901</startdate><enddate>20110901</enddate><creator>HASHIMOTO, Toru</creator><creator>ICHIKI, Toshihiro</creator><creator>IKEDA, Jiro</creator><creator>NARABAYASHI, Eriko</creator><creator>MATSUURA, Hirohide</creator><creator>MIYAZAKI, Ryohei</creator><creator>INANAGA, Keita</creator><creator>TAKEDA, Kotaro</creator><creator>SUNAGAWA, Kenji</creator><general>Oxford University Press</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>20110901</creationdate><title>Inhibition of MDM2 attenuates neointimal hyperplasia via suppression of vascular proliferation and inflammation</title><author>HASHIMOTO, Toru ; ICHIKI, Toshihiro ; IKEDA, Jiro ; NARABAYASHI, Eriko ; MATSUURA, Hirohide ; MIYAZAKI, Ryohei ; INANAGA, Keita ; TAKEDA, Kotaro ; SUNAGAWA, Kenji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-d70ce214125105f493ce5efa854fab48b5ca7f10f0aa87aaab5f7de36eb710e13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cardiology. Vascular system</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Movement - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Hyperplasia</topic><topic>Imidazoles - pharmacology</topic><topic>Inflammation - prevention & control</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Muscle, Smooth, Vascular - cytology</topic><topic>Neointima - pathology</topic><topic>NF-kappa B - metabolism</topic><topic>Piperazines - pharmacology</topic><topic>Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-mdm2 - physiology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Tumor Suppressor Protein p53 - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>HASHIMOTO, Toru</creatorcontrib><creatorcontrib>ICHIKI, Toshihiro</creatorcontrib><creatorcontrib>IKEDA, Jiro</creatorcontrib><creatorcontrib>NARABAYASHI, Eriko</creatorcontrib><creatorcontrib>MATSUURA, Hirohide</creatorcontrib><creatorcontrib>MIYAZAKI, Ryohei</creatorcontrib><creatorcontrib>INANAGA, Keita</creatorcontrib><creatorcontrib>TAKEDA, Kotaro</creatorcontrib><creatorcontrib>SUNAGAWA, Kenji</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>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>HASHIMOTO, Toru</au><au>ICHIKI, Toshihiro</au><au>IKEDA, Jiro</au><au>NARABAYASHI, Eriko</au><au>MATSUURA, Hirohide</au><au>MIYAZAKI, Ryohei</au><au>INANAGA, Keita</au><au>TAKEDA, Kotaro</au><au>SUNAGAWA, Kenji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of MDM2 attenuates neointimal hyperplasia via suppression of vascular proliferation and inflammation</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2011-09-01</date><risdate>2011</risdate><volume>91</volume><issue>4</issue><spage>711</spage><epage>719</epage><pages>711-719</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><coden>CVREAU</coden><abstract>Tumour protein p53 plays an important role in the vascular remodelling process as well as in oncogenesis. p53 is negatively regulated by murine double minute 2 (MDM2). A recently developed MDM2 inhibitor, nutlin-3, is a non-genotoxic activator of the p53 pathway. So far, the effect of MDM2 inhibition on vascular remodelling has not been elucidated. We therefore investigated the effect of nutlin-3 on neointima formation.
Nutlin-3 up-regulated p53 and its downstream target p21 in vascular smooth muscle cells (VSMCs). DNA synthesis assay and flow cytometric analysis revealed that nutlin-3 inhibited platelet-derived growth factor (PDGF)-induced VSMC proliferation by cell cycle arrest. This inhibitory effect was abrogated in p53-siRNA-transfected VSMCs. Furthermore, nutlin-3 inhibited PDGF-stimulated VSMC migration. Treatment with nutlin-3 attenuated neointimal hyperplasia at 28 days after vascular injury in mice, associated with up-regulation of p53 and p21. BrdU incorporation was decreased at 14 days after injury in nutlin-3-treated mice. TUNEL assay showed that nutlin-3 did not exaggerate apoptosis of the injured vessels. Infiltration of macrophages and T-lymphocytes and mRNA expression of chemokine (C-C motif) ligand-5, interleukin-6, and intercellular adhesion molecule-1 were decreased in the injured vessels of nutlin-3-treated mice. Nutlin-3 suppressed NF-κB activation in VSMCs, but not in p53-siRNA-transfected VSMCs.
The MDM2 antagonist nutlin-3 inhibits VSMC proliferation, migration, and NF-κB activation, and also attenuates neointimal hyperplasia after vascular injury in mice, which is associated with suppression of vascular cell proliferation and an inflammatory response. Targeting MDM2 might be a potential therapeutic strategy for the treatment of vascular proliferative diseases.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>21498419</pmid><doi>10.1093/cvr/cvr108</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological and medical sciences Cardiology. Vascular system Cell Cycle - drug effects Cell Movement - drug effects Cell Proliferation - drug effects Hyperplasia Imidazoles - pharmacology Inflammation - prevention & control Male Medical sciences Mice Mice, Inbred C57BL Muscle, Smooth, Vascular - cytology Neointima - pathology NF-kappa B - metabolism Piperazines - pharmacology Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors Proto-Oncogene Proteins c-mdm2 - physiology Rats Rats, Sprague-Dawley Tumor Suppressor Protein p53 - physiology |
| title | Inhibition of MDM2 attenuates neointimal hyperplasia via suppression of vascular proliferation and inflammation |
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