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Forkhead factor, FOXO3a, induces apoptosis of endothelial cells through activation of matrix metalloproteinases

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dc.contributor.authorLee, Hae-Young-
dc.contributor.authorYou, Hyun-Jung-
dc.contributor.authorWon, Joo-Yun-
dc.contributor.authorYoun, Seock-Won-
dc.contributor.authorCho, Hyun-Jai-
dc.contributor.authorPark, Kyung-Woo-
dc.contributor.authorPark, Woong-Yang-
dc.contributor.authorSeo, Jeong-Sun-
dc.contributor.authorPark, Young-Bae-
dc.contributor.authorWalsh, Kenneth-
dc.contributor.authorOh, Byung-Hee-
dc.contributor.authorKim, Hyo-Soo-
dc.date.accessioned2010-06-07-
dc.date.available2010-06-07-
dc.date.issued2007-12-08-
dc.identifier.citationArterioscler Thromb Vasc Biol. 2008;28(2):302-8en
dc.identifier.issn1524-4636 (Electronic)-
dc.identifier.urihttp://atvb.ahajournals.org/cgi/reprint/28/2/302.pdf-
dc.identifier.urihttps://hdl.handle.net/10371/67462-
dc.description.abstractBACKGROUND: The forkhead factor, FOXO3a, is known to induce apoptosis in endothelial cells (ECs). However, its effects on extracellular matrices (ECM), which are important in EC survival, remained unknown. Here, we evaluated the role of FOXO3a on EC-ECM interaction. METHODS AND RESULTS: Constitutively active FOXO3a was transduced to human umbilical vein endothelial cells by adenoviral vector (Ad-TM-FOXO3a). Ad-TM-FOXO3a transfection led to dehiscence of ECs from fibronectin-coated plates, resulting in anoikis, which was significantly reversed by matrix metalloproteinase (MMP) inhibitor, GM6001. FOXO3a increased the expression of MMP-3 (stromelysin-1) but decreased the expression of tissue inhibitors of metalloproteinases-1 (TIMP-1), which was associated with increased MMP enzymatic activity in zymography. Pathophysiologic conditions such as serum starvation or heat shock also induced activation of endogenous FOXO3a, leading to activation of MMP-3 and apoptosis, which was reversed by GM6001. Delivery of Ad-TM-FOXO3a to the intraluminal surface in vivo led to EC denudation, disrupted vascular integrity, and impaired endothelium-dependent vasorelaxation. CONCLUSIONS: Activation of MMPs and possible ECM disruption represent novel mechanisms of FOXO3a-mediated apoptosis in ECs.en
dc.language.isoenen
dc.publisherAmerican Heart Associationen
dc.subjectAnimalsen
dc.subjectAnoikis/physiologyen
dc.subjectApoptosis/*physiologyen
dc.subjectCarotid Arteries/physiologyen
dc.subjectCell Adhesion/physiologyen
dc.subjectCells, Cultureden
dc.subjectEndothelial Cells/*physiologyen
dc.subjectEnzyme Activationen
dc.subjectExtracellular Matrix/physiologyen
dc.subjectForkhead Transcription Factors/*physiologyen
dc.subjectHumansen
dc.subjectMatrix Metalloproteinase 3/*metabolismen
dc.subjectRabbitsen
dc.subjectTissue Inhibitor of Metalloproteinase-1/*metabolismen
dc.subjectUmbilical Veins/cytologyen
dc.titleForkhead factor, FOXO3a, induces apoptosis of endothelial cells through activation of matrix metalloproteinasesen
dc.typeArticleen
dc.contributor.AlternativeAuthor이해영-
dc.contributor.AlternativeAuthor유현정-
dc.contributor.AlternativeAuthor원주연-
dc.contributor.AlternativeAuthor윤석원-
dc.contributor.AlternativeAuthor조현재-
dc.contributor.AlternativeAuthor박경우-
dc.contributor.AlternativeAuthor박웅양-
dc.contributor.AlternativeAuthor서정선-
dc.contributor.AlternativeAuthor박영배-
dc.contributor.AlternativeAuthor오병희-
dc.contributor.AlternativeAuthor김효수-
dc.identifier.doi10.1161/ATVBAHA.107.150664-
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