{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:09:34Z","timestamp":1790622574616,"version":"4.1.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results\u2014<\/jats:title>\n            <jats:p>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\u2013induced 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\u2013induced 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.112.300922","type":"journal-article","created":{"date-parts":[[2013,5,3]],"date-time":"2013-05-03T07:52:21Z","timestamp":1367567541000},"page":"1591-1600","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":79,"title":["Statins Exert the Pleiotropic Effects Through Small GTP-Binding Protein Dissociation Stimulator Upregulation With a Resultant Rac1 Degradation"],"prefix":"10.1161","volume":"33","author":[{"given":"Shin-ichi","family":"Tanaka","sequence":"first","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.-i.T., Y.F., K.N., T.M., S.K., N.S., H.S.); Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan (Y.T.); Department of Pharmacology and Toxicology, Cardiovascular Center, Cancer Center, Medical College of Wisconsin, Milwaukee, WI (C.L.W.); and Section of Cardiology, The University of Chicago Medicine, Chicago, IL (J.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Fukumoto","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.-i.T., Y.F., K.N., T.M., S.K., N.S., H.S.); Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan (Y.T.); Department of Pharmacology and Toxicology, Cardiovascular Center, Cancer Center, Medical College of Wisconsin, Milwaukee, WI (C.L.W.); and Section of Cardiology, The University of Chicago Medicine, Chicago, IL (J.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Nochioka","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.-i.T., Y.F., K.N., T.M., S.K., N.S., H.S.); Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan (Y.T.); Department of Pharmacology and Toxicology, Cardiovascular Center, Cancer Center, Medical College of Wisconsin, Milwaukee, WI (C.L.W.); and Section of Cardiology, The University of Chicago Medicine, Chicago, IL (J.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuro","family":"Minami","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.-i.T., Y.F., K.N., T.M., S.K., N.S., H.S.); Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan (Y.T.); Department of Pharmacology and Toxicology, Cardiovascular Center, Cancer Center, Medical College of Wisconsin, Milwaukee, WI (C.L.W.); and Section of Cardiology, The University of Chicago Medicine, Chicago, IL (J.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Kudo","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.-i.T., Y.F., K.N., T.M., S.K., N.S., H.S.); Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan (Y.T.); Department of Pharmacology and Toxicology, Cardiovascular Center, Cancer Center, Medical College of Wisconsin, Milwaukee, WI (C.L.W.); and Section of Cardiology, The University of Chicago Medicine, Chicago, IL (J.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Shiba","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.-i.T., Y.F., K.N., T.M., S.K., N.S., H.S.); Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan (Y.T.); Department of Pharmacology and Toxicology, Cardiovascular Center, Cancer Center, Medical College of Wisconsin, Milwaukee, WI (C.L.W.); and Section of Cardiology, The University of Chicago Medicine, Chicago, IL (J.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimi","family":"Takai","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.-i.T., Y.F., K.N., T.M., S.K., N.S., H.S.); Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan (Y.T.); Department of Pharmacology and Toxicology, Cardiovascular Center, Cancer Center, Medical College of Wisconsin, Milwaukee, WI (C.L.W.); and Section of Cardiology, The University of Chicago Medicine, Chicago, IL (J.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol L.","family":"Williams","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.-i.T., Y.F., K.N., T.M., S.K., N.S., H.S.); Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan (Y.T.); Department of Pharmacology and Toxicology, Cardiovascular Center, Cancer Center, Medical College of Wisconsin, Milwaukee, WI (C.L.W.); and Section of Cardiology, The University of Chicago Medicine, Chicago, IL (J.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James K.","family":"Liao","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.-i.T., Y.F., K.N., T.M., S.K., N.S., H.S.); Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan (Y.T.); Department of Pharmacology and Toxicology, Cardiovascular Center, Cancer Center, Medical College of Wisconsin, Milwaukee, WI (C.L.W.); and Section of Cardiology, The University of Chicago Medicine, Chicago, IL (J.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Shimokawa","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.-i.T., Y.F., K.N., T.M., S.K., N.S., H.S.); Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan (Y.T.); Department of Pharmacology and Toxicology, Cardiovascular Center, Cancer Center, Medical College of Wisconsin, Milwaukee, WI (C.L.W.); and Section of Cardiology, The University of Chicago Medicine, Chicago, IL (J.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","first-page":"1383","article-title":"Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Survival Study (4S).","volume":"344","author":"Scandinavian Simvastatin Survival Study Group","year":"1994","unstructured":"Scandinavian Simvastatin Survival Study Group. 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