title: Effects of simvastatin on retinoic acid system in primary human endometrial stromal cells and in a chimeric model of human endometriosis.
abstract: BACKGROUND
  Retinoic acid (RA) may promote survival or apoptosis of cells, depending on the levels of binding proteins: apoptosis-inducing cellular RA binding protein 2 (CRABP2), and cell survival-promoting fatty acid binding protein 5 (FABP5). Increased cellular uptake of retinol and altered actions of RA related to reduced expression of CRABP2 may contribute to the development of endometriosis. Recently statins have been shown to inhibit growth of human endometrial stromal (HES) cells and to reduce the number and size of endometriotic implants in experimental models of this disorder.
  
  
  OBJECTIVE
  The objective of the study was to determine whether effects of simvastatin on HES cells and experimental endometriotic implants are related to the modulation of the RA system.
  
  
  METHODS
  Effects of simvastatin and RA on proliferation and apoptosis of HES cells were evaluated. Expression of stimulated by RA 6 (STRA6), CRABP2, and FABP5 was determined by real-time PCR and Western blotting. Effects of simvastatin were also evaluated in a nude mouse model of human endometriosis.
  
  
  RESULTS
  Simvastatin potentiated an inhibitory effect of RA on growth of HES cells. In HES cells, simvastatin induced expression of STRA6 and CRABP2 but not FABP5. Similarly, simvastatin treatment of nude mice bearing human endometrial xenografts led to an increased expression of CRABP2 and STRA6 proteins in ectopic lesions.
  
  
  CONCLUSIONS
  Simvastatin interacts with the RA system, inducing the expression of the key protein regulating the uptake of retinol (STRA6) and the expression of apoptosis-promoting CRABP2. These effects may contribute to cooperative apoptosis-inducing effects of simvastatin and RA and support the examination of these compounds in the treatment of endometriosis.
authors: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of California, Davis, Sacramento, California 95817, USA.
authors: Anna
authors: A
authors: Sokalska
authors: MariaPia
authors: M
authors: Anderson
authors: Jesus
authors: J
authors: Villanueva
authors: Israel
authors: I
authors: Ortega
authors: Kaylon L
authors: KL
authors: Bruner-Tran
authors: Kevin G
authors: KG
authors: Osteen
authors: Antoni J
authors: AJ
authors: Duleba
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002678:Chimera; D004195:Disease Models, Animal; D004715:Endometriosis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000166:cytology*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics; D061251:Primary Cell Culture; D018168:Receptors, Retinoic Acid / Q000235:genetics; D019821:Simvastatin / Q000494:pharmacology*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*
chemical_list: C493412:FABP5 protein, human; C082667:Fabp5 protein, mouse; D050556:Fatty Acid-Binding Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D018168:Receptors, Retinoic Acid; C519685:STRA6 protein, human; C108001:Stra6 protein, mouse; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin; D019821:Simvastatin