Simvastatin Stimulates Production of the Antiapoptotic Protein Bcl-2 via Endothelin-1 and NFATc3 in SH-SY5Y Cells
Identifieur interne : 000A18 ( Pmc/Checkpoint ); précédent : 000A17; suivant : 000A19Simvastatin Stimulates Production of the Antiapoptotic Protein Bcl-2 via Endothelin-1 and NFATc3 in SH-SY5Y Cells
Auteurs : Tammy A. Butterick ; Urule Igbavboa ; Gunter P. Eckert ; Grace Y. Sun ; Gary A. Weisman ; Walter E. Müller ; W. Gibson WoodSource :
- Molecular neurobiology [ 0893-7648 ] ; 2010.
Abstract
The use of statins for the prevention or treatment of different neurodegenerative diseases has generated considerable interest albeit with some controversy. Mechanisms of statin-induced neuroprotection are not well understood. Recently, we reported that simvastatin stimulated neuronal gene expression and protein levels of the major antiapoptotic protein Bcl-2 in vivo and in vitro; suppression of Bcl-2 in SH-SY5Y cells reduced simvastatin neuroprotection; effects were independent of cholesterol and other products of the 3-hydroxy-3-methylglutaryl-CoA reductase pathway. Endothelin-1 (ET-1) can increase Bcl-2 abundance via the transcription factor nuclear factor of activated thymocytes (NFATc), and simvastatin was reported to increase ET-1 gene expression. We tested the hypothesis that simvastatin stimulation of Bcl-2 involves up-regulation of ET-1 and binding of NFATc to Bcl-2 promoter sites in SH-SY5Y human neuroblastoma cells. Simvastatin increased both intracellular and secreted ET-1 protein levels. Exogenous ET-1 increased Bcl-2 protein abundance, which was inhibited by ET-1 receptor antagonists. Simvastatin increased translocation of NFATc3 to the nucleus while reducing nuclear NFATc1 and having no effect on NFATc4. Endothelin-1 also increased NFATc3 levels in the nucleus, and this increase was inhibited by ET-1 receptor antagonists. Treatment of cells with simvastatin stimulated binding of NFATc3 to the Bcl-2 promoter. We report novel findings showing that up-regulation of Bcl-2 by simvastatin involves ET-1 and the transcription factor NFATc3. Discovering how statins can selectively alter a specific NFATc isoform that leads to an increase in an antiapoptotic protein will provide a new approach to understanding statin-induced neuroprotection and conditions outside the brain in which apoptosis contributes to pathophysiology.
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DOI: 10.1007/s12035-010-8122-8
PubMed: 20369390
PubMed Central: 3075856
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<author><name sortKey="Butterick, Tammy A" sort="Butterick, Tammy A" uniqKey="Butterick T" first="Tammy A." last="Butterick">Tammy A. Butterick</name>
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<author><name sortKey="Igbavboa, Urule" sort="Igbavboa, Urule" uniqKey="Igbavboa U" first="Urule" last="Igbavboa">Urule Igbavboa</name>
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<author><name sortKey="Eckert, Gunter P" sort="Eckert, Gunter P" uniqKey="Eckert G" first="Gunter P." last="Eckert">Gunter P. Eckert</name>
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<author><name sortKey="Sun, Grace Y" sort="Sun, Grace Y" uniqKey="Sun G" first="Grace Y." last="Sun">Grace Y. Sun</name>
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<author><name sortKey="Weisman, Gary A" sort="Weisman, Gary A" uniqKey="Weisman G" first="Gary A." last="Weisman">Gary A. Weisman</name>
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<author><name sortKey="Muller, Walter E" sort="Muller, Walter E" uniqKey="Muller W" first="Walter E." last="Müller">Walter E. Müller</name>
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<front><div type="abstract" xml:lang="en"><p id="P1">The use of statins for the prevention or treatment of different neurodegenerative diseases has generated considerable interest albeit with some controversy. Mechanisms of statin-induced neuroprotection are not well understood. Recently, we reported that simvastatin stimulated neuronal gene expression and protein levels of the major antiapoptotic protein Bcl-2 in vivo and in vitro; suppression of Bcl-2 in SH-SY5Y cells reduced simvastatin neuroprotection; effects were independent of cholesterol and other products of the 3-hydroxy-3-methylglutaryl-CoA reductase pathway. Endothelin-1 (ET-1) can increase Bcl-2 abundance via the transcription factor nuclear factor of activated thymocytes (NFATc), and simvastatin was reported to increase ET-1 gene expression. We tested the hypothesis that simvastatin stimulation of Bcl-2 involves up-regulation of ET-1 and binding of NFATc to Bcl-2 promoter sites in SH-SY5Y human neuroblastoma cells. Simvastatin increased both intracellular and secreted ET-1 protein levels. Exogenous ET-1 increased Bcl-2 protein abundance, which was inhibited by ET-1 receptor antagonists. Simvastatin increased translocation of NFATc3 to the nucleus while reducing nuclear NFATc1 and having no effect on NFATc4. Endothelin-1 also increased NFATc3 levels in the nucleus, and this increase was inhibited by ET-1 receptor antagonists. Treatment of cells with simvastatin stimulated binding of NFATc3 to the Bcl-2 promoter. We report novel findings showing that up-regulation of Bcl-2 by simvastatin involves ET-1 and the transcription factor NFATc3. Discovering how statins can selectively alter a specific NFATc isoform that leads to an increase in an antiapoptotic protein will provide a new approach to understanding statin-induced neuroprotection and conditions outside the brain in which apoptosis contributes to pathophysiology.</p>
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<pmc article-type="research-article" xml:lang="en"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">8900963</journal-id>
<journal-id journal-id-type="pubmed-jr-id">1466</journal-id>
<journal-id journal-id-type="nlm-ta">Mol Neurobiol</journal-id>
<journal-title-group><journal-title>Molecular neurobiology</journal-title>
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<article-id pub-id-type="doi">10.1007/s12035-010-8122-8</article-id>
<article-id pub-id-type="manuscript">NIHMS284040</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
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</article-categories>
<title-group><article-title>Simvastatin Stimulates Production of the Antiapoptotic Protein Bcl-2 via Endothelin-1 and NFATc3 in SH-SY5Y Cells</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Butterick</surname>
<given-names>Tammy A.</given-names>
</name>
<aff id="A1">Department of Pharmacology, Geriatric Research Education and Clinical Center, VA Medical Center, University of Minnesota, Minneapolis, MN, USA</aff>
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<contrib contrib-type="author"><name><surname>Igbavboa</surname>
<given-names>Urule</given-names>
</name>
<aff id="A2">Department of Pharmacology, Geriatric Research Education and Clinical Center, VA Medical Center, University of Minnesota, Minneapolis, MN, USA</aff>
</contrib>
<contrib contrib-type="author"><name><surname>Eckert</surname>
<given-names>Gunter P.</given-names>
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<aff id="A3">Department of Pharmacology, BiocenterNiederursel, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany</aff>
</contrib>
<contrib contrib-type="author"><name><surname>Sun</surname>
<given-names>Grace Y.</given-names>
</name>
<aff id="A4">Department of Biochemistry, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, Canada</aff>
</contrib>
<contrib contrib-type="author"><name><surname>Weisman</surname>
<given-names>Gary A.</given-names>
</name>
<aff id="A5">Department of Biochemistry, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, Canada</aff>
</contrib>
<contrib contrib-type="author"><name><surname>Müller</surname>
<given-names>Walter E.</given-names>
</name>
<aff id="A6">Department of Pharmacology, BiocenterNiederursel, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany</aff>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Wood</surname>
<given-names>W. Gibson</given-names>
</name>
<aff id="A7">Department of Pharmacology, Geriatric Research Education and Clinical Center, VA Medical Center, University of Minnesota, Minneapolis, MN, USA. Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street, SE, Minneapolis, MN 55455, USA</aff>
<email>woodx002@umn.edu</email>
</contrib>
</contrib-group>
<pub-date pub-type="nihms-submitted"><day>29</day>
<month>3</month>
<year>2011</year>
</pub-date>
<pub-date pub-type="epub"><day>6</day>
<month>4</month>
<year>2010</year>
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<pub-date pub-type="ppub"><month>6</month>
<year>2010</year>
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<pub-date pub-type="pmc-release"><day>13</day>
<month>4</month>
<year>2011</year>
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<volume>41</volume>
<issue>2-3</issue>
<fpage>384</fpage>
<lpage>391</lpage>
<permissions><copyright-statement>© Springer Science+Business Media, LLC 2010</copyright-statement>
<copyright-year>2010</copyright-year>
</permissions>
<abstract><p id="P1">The use of statins for the prevention or treatment of different neurodegenerative diseases has generated considerable interest albeit with some controversy. Mechanisms of statin-induced neuroprotection are not well understood. Recently, we reported that simvastatin stimulated neuronal gene expression and protein levels of the major antiapoptotic protein Bcl-2 in vivo and in vitro; suppression of Bcl-2 in SH-SY5Y cells reduced simvastatin neuroprotection; effects were independent of cholesterol and other products of the 3-hydroxy-3-methylglutaryl-CoA reductase pathway. Endothelin-1 (ET-1) can increase Bcl-2 abundance via the transcription factor nuclear factor of activated thymocytes (NFATc), and simvastatin was reported to increase ET-1 gene expression. We tested the hypothesis that simvastatin stimulation of Bcl-2 involves up-regulation of ET-1 and binding of NFATc to Bcl-2 promoter sites in SH-SY5Y human neuroblastoma cells. Simvastatin increased both intracellular and secreted ET-1 protein levels. Exogenous ET-1 increased Bcl-2 protein abundance, which was inhibited by ET-1 receptor antagonists. Simvastatin increased translocation of NFATc3 to the nucleus while reducing nuclear NFATc1 and having no effect on NFATc4. Endothelin-1 also increased NFATc3 levels in the nucleus, and this increase was inhibited by ET-1 receptor antagonists. Treatment of cells with simvastatin stimulated binding of NFATc3 to the Bcl-2 promoter. We report novel findings showing that up-regulation of Bcl-2 by simvastatin involves ET-1 and the transcription factor NFATc3. Discovering how statins can selectively alter a specific NFATc isoform that leads to an increase in an antiapoptotic protein will provide a new approach to understanding statin-induced neuroprotection and conditions outside the brain in which apoptosis contributes to pathophysiology.</p>
</abstract>
<kwd-group><kwd>Simvastatin</kwd>
<kwd>Bcl-2</kwd>
<kwd>Endothelin-1</kwd>
<kwd>Alzheimer’s disease</kwd>
<kwd>Statins</kwd>
<kwd>Neuroprotection</kwd>
<kwd>Apoptosis</kwd>
<kwd>NFAT</kwd>
</kwd-group>
<funding-group><award-group><funding-source country="United States">National Institute on Aging : NIA</funding-source>
<award-id>P01 AG018357-08 || AG</award-id>
</award-group>
</funding-group>
</article-meta>
</front>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey="Butterick, Tammy A" sort="Butterick, Tammy A" uniqKey="Butterick T" first="Tammy A." last="Butterick">Tammy A. Butterick</name>
<name sortKey="Eckert, Gunter P" sort="Eckert, Gunter P" uniqKey="Eckert G" first="Gunter P." last="Eckert">Gunter P. Eckert</name>
<name sortKey="Igbavboa, Urule" sort="Igbavboa, Urule" uniqKey="Igbavboa U" first="Urule" last="Igbavboa">Urule Igbavboa</name>
<name sortKey="Muller, Walter E" sort="Muller, Walter E" uniqKey="Muller W" first="Walter E." last="Müller">Walter E. Müller</name>
<name sortKey="Sun, Grace Y" sort="Sun, Grace Y" uniqKey="Sun G" first="Grace Y." last="Sun">Grace Y. Sun</name>
<name sortKey="Weisman, Gary A" sort="Weisman, Gary A" uniqKey="Weisman G" first="Gary A." last="Weisman">Gary A. Weisman</name>
<name sortKey="Wood, W Gibson" sort="Wood, W Gibson" uniqKey="Wood W" first="W. Gibson" last="Wood">W. Gibson Wood</name>
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