Statins exert the pleiotropic effects through small gtp-binding protein dissociation stimulator upregulation with a resultant rac1 degradation

Shin Ichi Tanaka, Yoshihiro Fukumoto, Kotaro Nochioka, Tatsuro Minami, Shun Kudo, Nobuyuki Shiba, Yoshimi Takai, Carol L. Williams, James K. Liao, Hiroaki Shimokawa

Research output: Contribution to journalArticle

49 Citations (Scopus)

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. Approach and 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 lipoproteincholesterol. 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.

Original languageEnglish
Pages (from-to)1591-1600
Number of pages10
JournalArteriosclerosis, thrombosis, and vascular biology
Volume33
Issue number7
DOIs
Publication statusPublished - 2013 Jul

Keywords

  • Rac
  • Reactive oxygen species
  • Rho
  • Small GTP-binding protein GDP dissociation stimulator
  • Statins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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