{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,11]],"date-time":"2026-01-11T18:02:40Z","timestamp":1768154560113,"version":"3.49.0"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Hypertension"],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:p>\n            The detailed molecular mechanisms of the pleiotropic effects of statins remain to be fully elucidated. Here, we hypothesized that cardioprotective effects of statins are mediated by small GTP-binding protein GDP dissociation stimulator (SmgGDS). SmgGDS\n            <jats:sup>+\/\u2013<\/jats:sup>\n            and wild-type (WT) mice were treated with continuous infusion of angiotensin II (Ang II) for 2 weeks with and without oral treatment with atorvastatin or pravastatin. At 2 weeks, the extents of Ang II\u2013induced cardiac hypertrophy and fibrosis were comparable between the 2 genotypes. However, statins significantly attenuated cardiomyocyte hypertrophy and fibrosis in WT mice, but not in SmgGDS\n            <jats:sup>+\/\u2013<\/jats:sup>\n            mice. In SmgGDS\n            <jats:sup>+\/\u2013<\/jats:sup>\n            cardiac fibroblasts (CFs), Rac1 expression, extracellular signal\u2013regulated kinases 1\/2 activity, Rho-kinase activity, and inflammatory cytokines secretion in response to Ang II were significantly increased when compared with WT CFs. Atorvastatin significantly reduced Rac1 expression and oxidative stress in WT CFs, but not in SmgGDS\n            <jats:sup>+\/\u2013<\/jats:sup>\n            CFs. Furthermore, Bio-plex analysis revealed significant upregulations of inflammatory cytokines\/chemokines and growth factors in SmgGDS\n            <jats:sup>+\/\u2013<\/jats:sup>\n            CFs when compared with WT CFs. Importantly, conditioned medium from SmgGDS\n            <jats:sup>+\/\u2013<\/jats:sup>\n            CFs increased B-type natriuretic peptide expression in rat cardiomyocytes to a greater extent than that from WT CFs. Furthermore, atorvastatin significantly increased SmgGDS secretion from mouse CFs. Finally, treatment with recombinant SmgGDS significantly reduced Rac1 expression in SmgGDS\n            <jats:sup>+\/\u2013<\/jats:sup>\n            CFs. These results indicate that both intracellular and extracellular SmgGDS play crucial roles in the inhibitory effects of statins on cardiac hypertrophy and fibrosis, partly through inhibition of Rac1, Rho kinase, and extracellular signal\u2013regulated kinase 1\/2 pathways, demonstrating the novel mechanism of the pleiotropic effects of statins.\n          <\/jats:p>","DOI":"10.1161\/hypertensionaha.115.07089","type":"journal-article","created":{"date-parts":[[2016,3,15]],"date-time":"2016-03-15T03:28:24Z","timestamp":1458012504000},"page":"878-889","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["SmgGDS as a Crucial Mediator of the Inhibitory Effects of Statins on Cardiac Hypertrophy and Fibrosis"],"prefix":"10.1161","volume":"67","author":[{"given":"Shun","family":"Kudo","sequence":"first","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimio","family":"Satoh","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masamichi","family":"Nogi","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kota","family":"Suzuki","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinichiro","family":"Sunamura","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junichi","family":"Omura","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuhiro","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Kurosawa","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taijyu","family":"Satoh","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 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