title: Simvastatin stimulates production of the antiapoptotic protein Bcl-2 via endothelin-1 and NFATc3 in SH-SY5Y cells.
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.
authors.affiliation: Department of Pharmacology, Geriatric Research Education and Clinical Center, VA Medical Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Tammy A
authors.initials: TA
authors.lastname: Butterick
authors.forename: Urule
authors.initials: U
authors.lastname: Igbavboa
authors.forename: Gunter P
authors.initials: GP
authors.lastname: Eckert
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Sun
authors.forename: Gary A
authors.initials: GA
authors.lastname: Weisman
authors.forename: Walter E
authors.initials: WE
authors.lastname: Müller
authors.forename: W Gibson
authors.initials: WG
authors.lastname: Wood
mesh_terms: D045744:Cell Line, Tumor / Q000187:drug effects* / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D019332:Endothelin-1; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C494008:NFATC3 protein, human; C494010:NFATC4 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D019821:Simvastatin