title: SmgGDS as a Crucial Mediator of the Inhibitory Effects of Statins on Cardiac Hypertrophy and Fibrosis: Novel Mechanism of the Pleiotropic Effects of Statins.
abstract: 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(+/-) 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-induced 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(+/-) mice. In SmgGDS(+/-) cardiac fibroblasts (CFs), Rac1 expression, extracellular signal-regulated 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(+/-) CFs. Furthermore, Bio-plex analysis revealed significant upregulations of inflammatory cytokines/chemokines and growth factors in SmgGDS(+/-) CFs when compared with WT CFs. Importantly, conditioned medium from SmgGDS(+/-) 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(+/-) 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-regulated kinase 1/2 pathways, demonstrating the novel mechanism of the pleiotropic effects of statins.
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Kudo
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kimio
authors.initials: K
authors.lastname: Satoh
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Nogi
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Sunamura
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Omura
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kikuchi
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Kurosawa
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Taijyu
authors.initials: T
authors.lastname: Satoh
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Minami
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyata
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. shimo@cardio.med.tohoku.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000378:metabolism* / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012380:Role; D013045:Species Specificity
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; D003598:Cytoskeletal Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017382:Reactive Oxygen Species; C100815:Kifap3 protein, mouse; D017035:Pravastatin
keywords: angiotensin II; chemokines; oxidative stress; pravastatin; statin