title: Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation.
abstract: OBJECTIVE
  The pleiotropic effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) independent of cholesterol-lowering effects are thought to be mediated through inhibition of the Rho/Rho-kinase pathway. However, we have previously demonstrated that the pleiotropic effects of regular-dose statins are mediated mainly through inhibition of the Rac1 signaling pathway rather than the Rho/Rho-kinase pathway, although the molecular mechanisms of the selective inhibition of the Rac1 signaling pathway by regular-dose statins remain to be elucidated. In this study, we tested our hypothesis that small GTP-binding protein GDP dissociation stimulator (SmgGDS) plays a crucial role in the molecular mechanisms of the Rac1 signaling pathway inhibition by statins in endothelial cells.
  
  
  RESULTS
  In cultured human umbilical venous endothelial cells, statins concentration-dependently increased SmgGDS expression and decreased nuclear Rac1. Statins also enhanced SmgGDS expression in mouse aorta. In control mice, the protective effects of statins against angiotensin II-induced medial thickening of coronary arteries and fibrosis were noted, whereas in SmgGDS-deficient mice, the protective effects of statins were absent. When SmgGDS was knocked down by its small interfering RNA in human umbilical venous endothelial cells, statins were no longer able to induce Rac1 degradation or inhibit angiotensin II-induced production of reactive oxygen species. Finally, in normal healthy volunteers, statins significantly increased SmgGDS expression with a significant negative correlation between SmgGDS expression and oxidative stress markers, whereas no correlation was noted with total or low-density lipoprotein-cholesterol.
  
  
  CONCLUSIONS
  These results indicate that statins exert their pleiotropic effects through SmgGDS upregulation with a resultant Rac1 degradation and reduced oxidative stress in animals and humans.
authors: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors: Shin-ichi
authors: S
authors: Tanaka
authors: Yoshihiro
authors: Y
authors: Fukumoto
authors: Kotaro
authors: K
authors: Nochioka
authors: Tatsuro
authors: T
authors: Minami
authors: Shun
authors: S
authors: Kudo
authors: Nobuyuki
authors: N
authors: Shiba
authors: Yoshimi
authors: Y
authors: Takai
authors: Carol L
authors: CL
authors: Williams
authors: James K
authors: JK
authors: Liao
authors: Hiroaki
authors: H
authors: Shimokawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000804:Angiotensin II; D000818:Animals; D000069059:Atorvastatin; D015415:Biomarkers / Q000097:blood; D006332:Cardiomegaly / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018592:Cross-Over Studies; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007564:Japan; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D008078:Cholesterol, LDL; D003598:Cytoskeletal Proteins; D020662:Guanine Nucleotide Exchange Factors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009479:Neuropeptides; D011758:Pyrroles; D011804:Quinolines; C107953:RAC1 protein, human; C115955:RAP1GDS1 protein, human; C484602:Rac1 protein, mouse; D000804:Angiotensin II; C100815:Kifap3 protein, mouse; D002784:Cholesterol; D000069059:Atorvastatin; D058539:Phosphatidylinositol 3-Kinase; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D017035:Pravastatin; C108475:pitavastatin
keywords: Rac; Rho; reactive oxygen species; small GTP-binding protein GDP dissociation stimulator; statins
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