Faculty Collaboration Database

Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation. Arterioscler Thromb Vasc Biol 2013 Jul;33(7):1591-600

Date

05/04/2013

Pubmed ID

23640485

Pubmed Central ID

PMC3863549

DOI

10.1161/ATVBAHA.112.300922

Scopus ID

2-s2.0-84879105232 (requires institutional sign-in at Scopus site)   73 Citations

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 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.

Author List

Tanaka S, Fukumoto Y, Nochioka K, Minami T, Kudo S, Shiba N, Takai Y, Williams CL, Liao JK, Shimokawa H

Author

Carol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Angiotensin II
Animals
Biomarkers
Cardiomegaly
Cells, Cultured
Cholesterol
Cholesterol, LDL
Coronary Vessels
Cross-Over Studies
Cytoskeletal Proteins
Disease Models, Animal
Dose-Response Relationship, Drug
Fibrosis
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
Guanine Nucleotide Exchange Factors
Heptanoic Acids
Human Umbilical Vein Endothelial Cells
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Japan
Male
Mice
Mice, Knockout
Neuropeptides
Oxidative Stress
Phosphatidylinositol 3-Kinase
Pravastatin
Proto-Oncogene Proteins c-akt
Pyrroles
Quinolines
RNA Interference
Signal Transduction
Transfection
rac GTP-Binding Proteins
rac1 GTP-Binding Protein