FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells
ABSTRACTEndothelial progenitor cells (EPCs) contribute to postnatal neovascularization. Risk factors for coronary artery disease reduce the number of EPCs in humans. Since EPC apoptosis might be a potential mechanism to regulate the number of EPCs, we investigated the effects of oxidative stress and...
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| Veröffentlicht in: | The FASEB journal 2005-06, Vol.19 (8), p.974-976 |
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| creator | Urbich, Carmen Knau, Andrea Fichtlscherer, Stephan Walter, Dirk H Brůhl, Thomas Potente, Michael Hofmann, Wolf K de Vos, Sven Zeiher, Andreas M Dimmeler, Stefanie |
| description | ABSTRACTEndothelial progenitor cells (EPCs) contribute to postnatal neovascularization. Risk factors for coronary artery disease reduce the number of EPCs in humans. Since EPC apoptosis might be a potential mechanism to regulate the number of EPCs, we investigated the effects of oxidative stress and HMG‐CoA‐reductase inhibitors (statins) on EPC apoptosis. Atorvastatin, mevastatin, or VEGF prevented EPC apoptosis induced by H2O2. The antiapoptotic effect was reversed by inhibition of the PI3K/Akt pathway. Forkhead transcription factors (FOXO1, FOXO3a, FOXO4) exert proapoptotic effects and are phosphorylated and, thereby, inactivated by Akt. Therefore, we elucidated the involvement of forkhead transcription factors. Atorvastatin induced the phosphorylation of the predominant forkhead factor FOXO4 in EPCs. In addition, atorvastatin reduced the expression of the proapoptotic forkhead‐regulated protein Bim in a PI3K‐dependent manner. Consistently, overexpression of FOXO4 activated the Bim promoter as determined by reporter gene expression and stimulated the expression of Bim, resulting in an increased EPC apoptosis. Statins failed to prevent EPC apoptosis induced by overexpression of Bim or nonphosphorylatable FOXO4, suggesting that the protective effects of statins depend on this pathway. In summary, our results show that FOXO‐dependent expression of Bim plays a pivotal role for EPC apoptosis. Statins reduce oxidative stress‐induced EPC apoptosis, inactivate FOXO4, and down‐regulate Bim. |
| doi_str_mv | 10.1096/fj.04-2727fje |
| format | Article |
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Risk factors for coronary artery disease reduce the number of EPCs in humans. Since EPC apoptosis might be a potential mechanism to regulate the number of EPCs, we investigated the effects of oxidative stress and HMG‐CoA‐reductase inhibitors (statins) on EPC apoptosis. Atorvastatin, mevastatin, or VEGF prevented EPC apoptosis induced by H2O2. The antiapoptotic effect was reversed by inhibition of the PI3K/Akt pathway. Forkhead transcription factors (FOXO1, FOXO3a, FOXO4) exert proapoptotic effects and are phosphorylated and, thereby, inactivated by Akt. Therefore, we elucidated the involvement of forkhead transcription factors. Atorvastatin induced the phosphorylation of the predominant forkhead factor FOXO4 in EPCs. In addition, atorvastatin reduced the expression of the proapoptotic forkhead‐regulated protein Bim in a PI3K‐dependent manner. Consistently, overexpression of FOXO4 activated the Bim promoter as determined by reporter gene expression and stimulated the expression of Bim, resulting in an increased EPC apoptosis. Statins failed to prevent EPC apoptosis induced by overexpression of Bim or nonphosphorylatable FOXO4, suggesting that the protective effects of statins depend on this pathway. In summary, our results show that FOXO‐dependent expression of Bim plays a pivotal role for EPC apoptosis. Statins reduce oxidative stress‐induced EPC apoptosis, inactivate FOXO4, and down‐regulate Bim.</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.04-2727fje</identifier><identifier>PMID: 15824087</identifier><language>eng</language><publisher>United States: Federation of American Societies for Experimental Biology</publisher><subject>Apoptosis - drug effects ; Apoptosis - physiology ; Apoptosis Regulatory Proteins - genetics ; Apoptosis Regulatory Proteins - physiology ; Atorvastatin Calcium ; Bcl-2-Like Protein 11 ; cell death ; Cell Line ; Cell Survival - drug effects ; Cells, Cultured ; Endothelial Cells - physiology ; Flow Cytometry ; forkhead transcription factors ; Gene Expression - drug effects ; Heptanoic Acids - pharmacology ; Humans ; Hydrogen Peroxide - pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology ; Leukocytes, Mononuclear ; Membrane Proteins - genetics ; Membrane Proteins - physiology ; Oxidative Stress ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylation ; PI3K/Akt signaling ; Promoter Regions, Genetic - genetics ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - physiology ; Pyrroles - pharmacology ; statins ; Stem Cells - physiology ; Transcription Factors - physiology ; Transfection ; Umbilical Veins</subject><ispartof>The FASEB journal, 2005-06, Vol.19 (8), p.974-976</ispartof><rights>FASEB</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c432E-23753e7b9871088b96d472abe5f35a8de4695d79b92522c96f48fbfc46660df93</citedby><cites>FETCH-LOGICAL-c432E-23753e7b9871088b96d472abe5f35a8de4695d79b92522c96f48fbfc46660df93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.04-2727fje$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.04-2727fje$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15824087$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Urbich, Carmen</creatorcontrib><creatorcontrib>Knau, Andrea</creatorcontrib><creatorcontrib>Fichtlscherer, Stephan</creatorcontrib><creatorcontrib>Walter, Dirk H</creatorcontrib><creatorcontrib>Brůhl, Thomas</creatorcontrib><creatorcontrib>Potente, Michael</creatorcontrib><creatorcontrib>Hofmann, Wolf K</creatorcontrib><creatorcontrib>de Vos, Sven</creatorcontrib><creatorcontrib>Zeiher, Andreas M</creatorcontrib><creatorcontrib>Dimmeler, Stefanie</creatorcontrib><title>FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>ABSTRACTEndothelial progenitor cells (EPCs) contribute to postnatal neovascularization. Risk factors for coronary artery disease reduce the number of EPCs in humans. Since EPC apoptosis might be a potential mechanism to regulate the number of EPCs, we investigated the effects of oxidative stress and HMG‐CoA‐reductase inhibitors (statins) on EPC apoptosis. Atorvastatin, mevastatin, or VEGF prevented EPC apoptosis induced by H2O2. The antiapoptotic effect was reversed by inhibition of the PI3K/Akt pathway. Forkhead transcription factors (FOXO1, FOXO3a, FOXO4) exert proapoptotic effects and are phosphorylated and, thereby, inactivated by Akt. Therefore, we elucidated the involvement of forkhead transcription factors. Atorvastatin induced the phosphorylation of the predominant forkhead factor FOXO4 in EPCs. In addition, atorvastatin reduced the expression of the proapoptotic forkhead‐regulated protein Bim in a PI3K‐dependent manner. Consistently, overexpression of FOXO4 activated the Bim promoter as determined by reporter gene expression and stimulated the expression of Bim, resulting in an increased EPC apoptosis. Statins failed to prevent EPC apoptosis induced by overexpression of Bim or nonphosphorylatable FOXO4, suggesting that the protective effects of statins depend on this pathway. In summary, our results show that FOXO‐dependent expression of Bim plays a pivotal role for EPC apoptosis. Statins reduce oxidative stress‐induced EPC apoptosis, inactivate FOXO4, and down‐regulate Bim.</description><subject>Apoptosis - drug effects</subject><subject>Apoptosis - physiology</subject><subject>Apoptosis Regulatory Proteins - genetics</subject><subject>Apoptosis Regulatory Proteins - physiology</subject><subject>Atorvastatin Calcium</subject><subject>Bcl-2-Like Protein 11</subject><subject>cell death</subject><subject>Cell Line</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Endothelial Cells - physiology</subject><subject>Flow Cytometry</subject><subject>forkhead transcription factors</subject><subject>Gene Expression - drug effects</subject><subject>Heptanoic Acids - pharmacology</subject><subject>Humans</subject><subject>Hydrogen Peroxide - pharmacology</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology</subject><subject>Leukocytes, Mononuclear</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - physiology</subject><subject>Oxidative Stress</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>PI3K/Akt signaling</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - physiology</subject><subject>Pyrroles - pharmacology</subject><subject>statins</subject><subject>Stem Cells - physiology</subject><subject>Transcription Factors - physiology</subject><subject>Transfection</subject><subject>Umbilical Veins</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1v1DAQhi0EotvCkSv4xC3FX_FHb7TaFKpKeyiVuFlOMl68ysbBzhZ64q_jVVbixmVGIz3zaPQOQu8ouaTEyE9-d0lExRRTfgcv0IrWnFRSS_ISrYg2rJKS6zN0nvOOEEIJla_RGa01E0SrFfrTbL5vqh4mGHsYZwy_pwQ5hzji6PH8A_CUopviNMc5dMdhhjDi67C_wlN4irMbcIoDYB8TXrgcMs5hO7ohjFtc4KKOxTSEwhbBFsYwF7qDYchv0CvvhgxvT_0CPTbrbzdfqvvN7debz_dVJzhbV4yrmoNqjVaUaN0a2QvFXAu157XTPQhp6l6Z1rCasc5IL7RvfSeklKT3hl-gj4u3HPDzAHm2-5CPF7gR4iFbqbQu0YkCVgvYpZhzAm-nFPYuPVtK7DFx63eWCHtKvPDvT-JDu4f-H32KuABXC_ArDPD8f5ttHq5Zc0fEcW7u1mX5w7LsXbRum0K2jw-MUF4-Waoi_C_8cZpd</recordid><startdate>200506</startdate><enddate>200506</enddate><creator>Urbich, Carmen</creator><creator>Knau, Andrea</creator><creator>Fichtlscherer, Stephan</creator><creator>Walter, Dirk H</creator><creator>Brůhl, Thomas</creator><creator>Potente, Michael</creator><creator>Hofmann, Wolf K</creator><creator>de Vos, Sven</creator><creator>Zeiher, Andreas M</creator><creator>Dimmeler, Stefanie</creator><general>Federation of American Societies for Experimental Biology</general><scope>FBQ</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>200506</creationdate><title>FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells</title><author>Urbich, Carmen ; Knau, Andrea ; Fichtlscherer, Stephan ; Walter, Dirk H ; Brůhl, Thomas ; Potente, Michael ; Hofmann, Wolf K ; de Vos, Sven ; Zeiher, Andreas M ; Dimmeler, Stefanie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c432E-23753e7b9871088b96d472abe5f35a8de4695d79b92522c96f48fbfc46660df93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Apoptosis - drug effects</topic><topic>Apoptosis - physiology</topic><topic>Apoptosis Regulatory Proteins - genetics</topic><topic>Apoptosis Regulatory Proteins - physiology</topic><topic>Atorvastatin Calcium</topic><topic>Bcl-2-Like Protein 11</topic><topic>cell death</topic><topic>Cell Line</topic><topic>Cell Survival - drug effects</topic><topic>Cells, Cultured</topic><topic>Endothelial Cells - physiology</topic><topic>Flow Cytometry</topic><topic>forkhead transcription factors</topic><topic>Gene Expression - drug effects</topic><topic>Heptanoic Acids - pharmacology</topic><topic>Humans</topic><topic>Hydrogen Peroxide - pharmacology</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology</topic><topic>Leukocytes, Mononuclear</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - physiology</topic><topic>Oxidative Stress</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphorylation</topic><topic>PI3K/Akt signaling</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins - physiology</topic><topic>Pyrroles - pharmacology</topic><topic>statins</topic><topic>Stem Cells - physiology</topic><topic>Transcription Factors - physiology</topic><topic>Transfection</topic><topic>Umbilical Veins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Urbich, Carmen</creatorcontrib><creatorcontrib>Knau, Andrea</creatorcontrib><creatorcontrib>Fichtlscherer, Stephan</creatorcontrib><creatorcontrib>Walter, Dirk H</creatorcontrib><creatorcontrib>Brůhl, Thomas</creatorcontrib><creatorcontrib>Potente, Michael</creatorcontrib><creatorcontrib>Hofmann, Wolf K</creatorcontrib><creatorcontrib>de Vos, Sven</creatorcontrib><creatorcontrib>Zeiher, Andreas M</creatorcontrib><creatorcontrib>Dimmeler, Stefanie</creatorcontrib><collection>AGRIS</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>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Urbich, Carmen</au><au>Knau, Andrea</au><au>Fichtlscherer, Stephan</au><au>Walter, Dirk H</au><au>Brůhl, Thomas</au><au>Potente, Michael</au><au>Hofmann, Wolf K</au><au>de Vos, Sven</au><au>Zeiher, Andreas M</au><au>Dimmeler, Stefanie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2005-06</date><risdate>2005</risdate><volume>19</volume><issue>8</issue><spage>974</spage><epage>976</epage><pages>974-976</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>ABSTRACTEndothelial progenitor cells (EPCs) contribute to postnatal neovascularization. Risk factors for coronary artery disease reduce the number of EPCs in humans. Since EPC apoptosis might be a potential mechanism to regulate the number of EPCs, we investigated the effects of oxidative stress and HMG‐CoA‐reductase inhibitors (statins) on EPC apoptosis. Atorvastatin, mevastatin, or VEGF prevented EPC apoptosis induced by H2O2. The antiapoptotic effect was reversed by inhibition of the PI3K/Akt pathway. Forkhead transcription factors (FOXO1, FOXO3a, FOXO4) exert proapoptotic effects and are phosphorylated and, thereby, inactivated by Akt. Therefore, we elucidated the involvement of forkhead transcription factors. Atorvastatin induced the phosphorylation of the predominant forkhead factor FOXO4 in EPCs. In addition, atorvastatin reduced the expression of the proapoptotic forkhead‐regulated protein Bim in a PI3K‐dependent manner. Consistently, overexpression of FOXO4 activated the Bim promoter as determined by reporter gene expression and stimulated the expression of Bim, resulting in an increased EPC apoptosis. Statins failed to prevent EPC apoptosis induced by overexpression of Bim or nonphosphorylatable FOXO4, suggesting that the protective effects of statins depend on this pathway. In summary, our results show that FOXO‐dependent expression of Bim plays a pivotal role for EPC apoptosis. Statins reduce oxidative stress‐induced EPC apoptosis, inactivate FOXO4, and down‐regulate Bim.</abstract><cop>United States</cop><pub>Federation of American Societies for Experimental Biology</pub><pmid>15824087</pmid><doi>10.1096/fj.04-2727fje</doi><tpages>3</tpages></addata></record> |
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| subjects | Apoptosis - drug effects Apoptosis - physiology Apoptosis Regulatory Proteins - genetics Apoptosis Regulatory Proteins - physiology Atorvastatin Calcium Bcl-2-Like Protein 11 cell death Cell Line Cell Survival - drug effects Cells, Cultured Endothelial Cells - physiology Flow Cytometry forkhead transcription factors Gene Expression - drug effects Heptanoic Acids - pharmacology Humans Hydrogen Peroxide - pharmacology Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology Leukocytes, Mononuclear Membrane Proteins - genetics Membrane Proteins - physiology Oxidative Stress Phosphatidylinositol 3-Kinases - metabolism Phosphorylation PI3K/Akt signaling Promoter Regions, Genetic - genetics Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - physiology Pyrroles - pharmacology statins Stem Cells - physiology Transcription Factors - physiology Transfection Umbilical Veins |
| title | FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells |
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