title: Resveratrol potentiates effect of simvastatin on inhibition of mevalonate pathway in human endometrial stromal cells.
abstract: BACKGROUND
  Growth of endometriotic lesions in rodent model of endometriosis is inhibited by resveratrol, a natural polyphenol with antiproliferative and antiinflammatory properties, and simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) activity.
  
  
  OBJECTIVE
  The objective of the investigation was to study the mechanism of action of resveratrol and its interactions with simvastatin, focusing on cholesterol biosynthesis and HMGCR gene expression and protein activity in primary cultures of human endometrial stromal (HES) cells.
  
  
  METHODS
  HES cells were obtained from healthy volunteers. Biosynthesis of cholesterol was assessed by measuring the conversion of [(14)C]acetate to [(14)C]cholesterol. HMGCR mRNA transcripts were quantified by real-time PCR, protein expression by Western blot analysis, and enzyme activity by measuring the conversion of [3-(14)C]3-hydroxy-3-methyl-glutaryl-coenzyme A to [(14)C]mevalonic acid lactone in HES cell microsomes.
  
  
  RESULTS
  Resveratrol inhibited cholesterol biosynthesis, HMGCR mRNA, and enzyme activity. Simvastatin inhibited cholesterol biosynthesis and enzyme activity but increased HMGCR mRNA and protein expression. Resveratrol potentiated the inhibitory effects of simvastatin on cholesterol biosynthesis and HMGCR enzyme activity and abrogated the stimulatory effects of simvastatin on HMGCR mRNA transcripts and protein expression.
  
  
  CONCLUSIONS
  Resveratrol inhibits key steps of the mevalonate pathway by mechanisms that are partly complementary to and partly comparable with simvastatin via reducing both expression and activity of HMGCR. A combination of resveratrol and simvastatin may be of potential clinical relevance to development new treatments of human endometriosis.
authors: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of California, Davis, Sacramento, California 95817, USA.
authors: Jesus A
authors: JA
authors: Villanueva
authors: Anna
authors: A
authors: Sokalska
authors: Amanda B
authors: AB
authors: Cress
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: D000085:Acetates / Q000378:metabolism; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002250:Carbon Radioisotopes; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism; D004357:Drug Synergism; D004717:Endometrium / Q000166:cytology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism*; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000378:metabolism; D000077185:Resveratrol; D019821:Simvastatin / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000085:Acetates; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002250:Carbon Radioisotopes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D013267:Stilbenes; D002784:Cholesterol; D019821:Simvastatin; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases; D000077185:Resveratrol; D008798:Mevalonic Acid
references: Adv Enzyme Regul. 1982;20:263-83
references: 7051770
references: J Pharmacol Exp Ther. 2000 Sep;294(3):1043-6
references: 10945857
references: J Biol Chem. 1988 Jun 25;263(18):8929-37
references: 3379053
references: J Clin Endocrinol Metab. 2010 Jul;95(7):3453-9
references: 20427495
references: Clin Exp Immunol. 2007 Jan;147(1):155-63
references: 17177975
references: Biochim Biophys Acta. 2004 Jan 28;1660(1-2):171-99
references: 14757233
references: Ann N Y Acad Sci. 2002 Mar;955:183-98; discussion 19-200, 396-406
references: 11949947
references: Arterioscler Thromb Vasc Biol. 2009 Mar;29(3):380-6
references: 19122173
references: Biol Reprod. 2006 Jul;75(1):107-11
references: 16571871
references: J Exp Med. 1977 Jun 1;145(6):1531-49
references: 194011
references: Nature. 1990 Feb 1;343(6257):425-30
references: 1967820
references: Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G833-42
references: 18755807
references: Fertil Steril. 2009 Dec;92(6):2097-9
references: 19643402
references: Biol Reprod. 2011 Jan;84(1):106-12
references: 20844278
references: Eur J Pharmacol. 2010 Jun 10;635(1-3):1-8
references: 20303945
references: Lipids. 1999 Dec;34(12):1327-32
references: 10652993
references: Biochem Biophys Res Commun. 2008 Sep 12;374(1):55-9
references: 18611391
references: Fertil Steril. 2007 Feb;87(2):257-62
references: 17097652
references: J Gerontol A Biol Sci Med Sci. 2012 Dec;67(12):1307-12
references: 22219517
references: J Med Food. 2008 Dec;11(4):773-83
references: 19053873
references: Biochim Biophys Acta. 1998 Jan 23;1389(3):213-21
references: 9512650
references: Arch Intern Med. 2012 Jan 23;172(2):144-52
references: 22231607
references: Biochem Biophys Res Commun. 2008 Feb 29;367(1):190-4
references: 18166149
references: Fertil Steril. 2011 Nov;96(5):1252-8
references: 21907337
references: Carcinogenesis. 2006 Jul;27(7):1465-74
references: 16474181
references: Nature. 2006 Nov 16;444(7117):337-42
references: 17086191
references: Br J Nutr. 2011 Aug;106(3):383-9
references: 21385509
references: Mol Cancer Ther. 2005 Apr;4(4):554-61
references: 15827328
references: Biol Reprod. 2012 Jul 05;87(1):2, 1-6
references: 22492974
references: Biomed Pharmacother. 2008 Nov;62(9):598-605
references: 18675532
references: Circulation. 2003 Jul 29;108(4):426-31
references: 12860913
references: J Lipid Res. 1985 Jul;26(7):831-41
references: 2411835
references: EMBO J. 1990 Aug;9(8):2439-46
references: 2369897
references: J Biol Chem. 1983 Jun 25;258(12):7272-5
references: 6863245
references: J Nutr. 2007 Dec;137(12):2668-73
references: 18029481
references: J Clin Endocrinol Metab. 2009 Jul;94(7):2489-94
references: 19366846
references: Diabetes. 2010 Mar;59(3):554-63
references: 19934007