In vitro investigation of integrin-receptor antagonist-induced vascular toxicity in the mouse
► This study examined the effects of SB-273005 on murine EC and VSMC monocultures and cocultures. ► SB-273005-induced aortic VSMC toxicity is not mediated or enhanced through EC/VSMC interactions. ► A direct effect of SB-273005 on mouse VSMC was observed. ► SB-273005 induced an increase in cytotoxic...
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Veröffentlicht in: | Toxicology in vitro 2013-02, Vol.27 (1), p.272-281 |
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description | ► This study examined the effects of SB-273005 on murine EC and VSMC monocultures and cocultures. ► SB-273005-induced aortic VSMC toxicity is not mediated or enhanced through EC/VSMC interactions. ► A direct effect of SB-273005 on mouse VSMC was observed. ► SB-273005 induced an increase in cytotoxicity and caspase-3/7 and -9 activity in VSMC monocultures. ► SB-273005-induced toxicity in VSMC cultures is mediated through the intrinsic apoptotic pathway.
An αVβ3 receptor antagonist (SB-273005) induced unique vascular lesions in the aorta of mice, but not other pharmacologically responsive species. Vascular smooth muscle cell (VSMC) necrosis was observed ∼6h postdose followed by VSMC loss with no evidence of hemorrhage/thrombosis, inflammation or damage to endothelium. Since direct drug-induced vascular toxicity is uncommon, involvement of VSMC–endothelial cell (EC) interactions was hypothesized. In vitro model systems of murine aortic VSMC and EC monocultures and cocultures were established and used to investigate the mechanism of toxicity. Incubation of cultures with SB-273005 within a dose range and timeframe comparable to in vivo studies, showed a concentration-dependent decrease in viability with increases in cytotoxicity for monocultures and VSMC/EC cocultures; however, VSMC monocultures responded at lower doses (were most sensitive) suggesting a direct effect on VSMC which is not mediated or enhanced through EC/VSMC interactions. Further studies revealed increased caspase-9 and caspase-3/7 activation in VSMC beginning as early as 0.5 and 1h following treatment, respectively. These findings suggest SB-273005 causes direct chemical vascular toxicity in murine VSMC which involves apoptosis mediated through the intrinsic (mitochondrial) apoptotic pathway. To our knowledge, this is the first report to provide a link between VSMC apoptosis and treatment with an αVβ3 receptor antagonist. |
doi_str_mv | 10.1016/j.tiv.2012.08.028 |
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An αVβ3 receptor antagonist (SB-273005) induced unique vascular lesions in the aorta of mice, but not other pharmacologically responsive species. Vascular smooth muscle cell (VSMC) necrosis was observed ∼6h postdose followed by VSMC loss with no evidence of hemorrhage/thrombosis, inflammation or damage to endothelium. Since direct drug-induced vascular toxicity is uncommon, involvement of VSMC–endothelial cell (EC) interactions was hypothesized. In vitro model systems of murine aortic VSMC and EC monocultures and cocultures were established and used to investigate the mechanism of toxicity. Incubation of cultures with SB-273005 within a dose range and timeframe comparable to in vivo studies, showed a concentration-dependent decrease in viability with increases in cytotoxicity for monocultures and VSMC/EC cocultures; however, VSMC monocultures responded at lower doses (were most sensitive) suggesting a direct effect on VSMC which is not mediated or enhanced through EC/VSMC interactions. Further studies revealed increased caspase-9 and caspase-3/7 activation in VSMC beginning as early as 0.5 and 1h following treatment, respectively. These findings suggest SB-273005 causes direct chemical vascular toxicity in murine VSMC which involves apoptosis mediated through the intrinsic (mitochondrial) apoptotic pathway. To our knowledge, this is the first report to provide a link between VSMC apoptosis and treatment with an αVβ3 receptor antagonist.</description><identifier>ISSN: 0887-2333</identifier><identifier>EISSN: 1879-3177</identifier><identifier>DOI: 10.1016/j.tiv.2012.08.028</identifier><identifier>PMID: 22964516</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Aorta - cytology ; Apoptosis - drug effects ; Caspases - metabolism ; Cell Survival - drug effects ; Cells, Cultured ; Coculture Techniques ; Endothelial cells ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; Integrin alphaVbeta3 - antagonists & inhibitors ; Mice ; Muscle, Smooth, Vascular - cytology ; Myocytes, Smooth Muscle - drug effects ; Myocytes, Smooth Muscle - metabolism ; Pyridines - pharmacology ; SB-273005 ; Vascular injury ; Vascular smooth muscle cells ; αVβ3 receptor antagonist</subject><ispartof>Toxicology in vitro, 2013-02, Vol.27 (1), p.272-281</ispartof><rights>2012 Elsevier Ltd</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c489t-b53e3bce3f9adf97b1a15961ea88c5c45a33d8d74a8f17c4594d05bde5b756063</citedby><cites>FETCH-LOGICAL-c489t-b53e3bce3f9adf97b1a15961ea88c5c45a33d8d74a8f17c4594d05bde5b756063</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0887233312002500$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22964516$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dalmas Wilk, Deidre A.</creatorcontrib><creatorcontrib>Scicchitano, Marshall S.</creatorcontrib><creatorcontrib>Morel, Diane</creatorcontrib><title>In vitro investigation of integrin-receptor antagonist-induced vascular toxicity in the mouse</title><title>Toxicology in vitro</title><addtitle>Toxicol In Vitro</addtitle><description>► This study examined the effects of SB-273005 on murine EC and VSMC monocultures and cocultures. ► SB-273005-induced aortic VSMC toxicity is not mediated or enhanced through EC/VSMC interactions. ► A direct effect of SB-273005 on mouse VSMC was observed. ► SB-273005 induced an increase in cytotoxicity and caspase-3/7 and -9 activity in VSMC monocultures. ► SB-273005-induced toxicity in VSMC cultures is mediated through the intrinsic apoptotic pathway.
An αVβ3 receptor antagonist (SB-273005) induced unique vascular lesions in the aorta of mice, but not other pharmacologically responsive species. Vascular smooth muscle cell (VSMC) necrosis was observed ∼6h postdose followed by VSMC loss with no evidence of hemorrhage/thrombosis, inflammation or damage to endothelium. Since direct drug-induced vascular toxicity is uncommon, involvement of VSMC–endothelial cell (EC) interactions was hypothesized. In vitro model systems of murine aortic VSMC and EC monocultures and cocultures were established and used to investigate the mechanism of toxicity. Incubation of cultures with SB-273005 within a dose range and timeframe comparable to in vivo studies, showed a concentration-dependent decrease in viability with increases in cytotoxicity for monocultures and VSMC/EC cocultures; however, VSMC monocultures responded at lower doses (were most sensitive) suggesting a direct effect on VSMC which is not mediated or enhanced through EC/VSMC interactions. Further studies revealed increased caspase-9 and caspase-3/7 activation in VSMC beginning as early as 0.5 and 1h following treatment, respectively. These findings suggest SB-273005 causes direct chemical vascular toxicity in murine VSMC which involves apoptosis mediated through the intrinsic (mitochondrial) apoptotic pathway. To our knowledge, this is the first report to provide a link between VSMC apoptosis and treatment with an αVβ3 receptor antagonist.</description><subject>Animals</subject><subject>Aorta - cytology</subject><subject>Apoptosis - drug effects</subject><subject>Caspases - metabolism</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Coculture Techniques</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - metabolism</subject><subject>Integrin alphaVbeta3 - antagonists & inhibitors</subject><subject>Mice</subject><subject>Muscle, Smooth, Vascular - cytology</subject><subject>Myocytes, Smooth Muscle - drug effects</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Pyridines - pharmacology</subject><subject>SB-273005</subject><subject>Vascular injury</subject><subject>Vascular smooth muscle cells</subject><subject>αVβ3 receptor antagonist</subject><issn>0887-2333</issn><issn>1879-3177</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE9rGzEQxUVJqZ20HyCXsMdcdqs_q5WWnoJJG0Ogl_ZYhFaadWVsyZW0S_3tI2Mnx5yGGd57zPshdEtwQzDpvm6b7OaGYkIbLBtM5Qe0JFL0NSNCXKElllLUlDG2QNcpbTHGXFL8CS0o7buWk26J_qx9NbscQ-X8DCm7jc4u-CqM5ZBhE52vIxg45BAr7bPeBO9Srp23kwFbzTqZaadjlcN_Z1w-FluV_0K1D1OCz-jjqHcJvlzmDfr9_fHX6ql-_vljvXp4rk0r-1wPnAEbDLCx13bsxUA04X1HQEtpuGm5ZsxKK1otRyLK3rcW88ECHwTvcMdu0P059xDDv6nUUHuXDOx22kP5Q5G2p11LOkGLlJylJoaUIozqEN1ex6MiWJ2oqq0qVNWJqsJSFarFc3eJn4Y92DfHK8Yi-HYWQCk5O4gqGQe-AHIFXlY2uHfiXwDTcIoa</recordid><startdate>20130201</startdate><enddate>20130201</enddate><creator>Dalmas Wilk, Deidre A.</creator><creator>Scicchitano, Marshall S.</creator><creator>Morel, Diane</creator><general>Elsevier Ltd</general><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>7U7</scope><scope>C1K</scope></search><sort><creationdate>20130201</creationdate><title>In vitro investigation of integrin-receptor antagonist-induced vascular toxicity in the mouse</title><author>Dalmas Wilk, Deidre A. ; Scicchitano, Marshall S. ; Morel, Diane</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c489t-b53e3bce3f9adf97b1a15961ea88c5c45a33d8d74a8f17c4594d05bde5b756063</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Aorta - cytology</topic><topic>Apoptosis - drug effects</topic><topic>Caspases - metabolism</topic><topic>Cell Survival - drug effects</topic><topic>Cells, Cultured</topic><topic>Coculture Techniques</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - metabolism</topic><topic>Integrin alphaVbeta3 - antagonists & inhibitors</topic><topic>Mice</topic><topic>Muscle, Smooth, Vascular - cytology</topic><topic>Myocytes, Smooth Muscle - drug effects</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Pyridines - pharmacology</topic><topic>SB-273005</topic><topic>Vascular injury</topic><topic>Vascular smooth muscle cells</topic><topic>αVβ3 receptor antagonist</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dalmas Wilk, Deidre A.</creatorcontrib><creatorcontrib>Scicchitano, Marshall S.</creatorcontrib><creatorcontrib>Morel, Diane</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Toxicology in vitro</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dalmas Wilk, Deidre A.</au><au>Scicchitano, Marshall S.</au><au>Morel, Diane</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vitro investigation of integrin-receptor antagonist-induced vascular toxicity in the mouse</atitle><jtitle>Toxicology in vitro</jtitle><addtitle>Toxicol In Vitro</addtitle><date>2013-02-01</date><risdate>2013</risdate><volume>27</volume><issue>1</issue><spage>272</spage><epage>281</epage><pages>272-281</pages><issn>0887-2333</issn><eissn>1879-3177</eissn><abstract>► This study examined the effects of SB-273005 on murine EC and VSMC monocultures and cocultures. ► SB-273005-induced aortic VSMC toxicity is not mediated or enhanced through EC/VSMC interactions. ► A direct effect of SB-273005 on mouse VSMC was observed. ► SB-273005 induced an increase in cytotoxicity and caspase-3/7 and -9 activity in VSMC monocultures. ► SB-273005-induced toxicity in VSMC cultures is mediated through the intrinsic apoptotic pathway.
An αVβ3 receptor antagonist (SB-273005) induced unique vascular lesions in the aorta of mice, but not other pharmacologically responsive species. Vascular smooth muscle cell (VSMC) necrosis was observed ∼6h postdose followed by VSMC loss with no evidence of hemorrhage/thrombosis, inflammation or damage to endothelium. Since direct drug-induced vascular toxicity is uncommon, involvement of VSMC–endothelial cell (EC) interactions was hypothesized. In vitro model systems of murine aortic VSMC and EC monocultures and cocultures were established and used to investigate the mechanism of toxicity. Incubation of cultures with SB-273005 within a dose range and timeframe comparable to in vivo studies, showed a concentration-dependent decrease in viability with increases in cytotoxicity for monocultures and VSMC/EC cocultures; however, VSMC monocultures responded at lower doses (were most sensitive) suggesting a direct effect on VSMC which is not mediated or enhanced through EC/VSMC interactions. Further studies revealed increased caspase-9 and caspase-3/7 activation in VSMC beginning as early as 0.5 and 1h following treatment, respectively. These findings suggest SB-273005 causes direct chemical vascular toxicity in murine VSMC which involves apoptosis mediated through the intrinsic (mitochondrial) apoptotic pathway. To our knowledge, this is the first report to provide a link between VSMC apoptosis and treatment with an αVβ3 receptor antagonist.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>22964516</pmid><doi>10.1016/j.tiv.2012.08.028</doi><tpages>10</tpages></addata></record> |
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subjects | Animals Aorta - cytology Apoptosis - drug effects Caspases - metabolism Cell Survival - drug effects Cells, Cultured Coculture Techniques Endothelial cells Endothelial Cells - drug effects Endothelial Cells - metabolism Integrin alphaVbeta3 - antagonists & inhibitors Mice Muscle, Smooth, Vascular - cytology Myocytes, Smooth Muscle - drug effects Myocytes, Smooth Muscle - metabolism Pyridines - pharmacology SB-273005 Vascular injury Vascular smooth muscle cells αVβ3 receptor antagonist |
title | In vitro investigation of integrin-receptor antagonist-induced vascular toxicity in the mouse |
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