SmgGDS as a Crucial Mediator of the Inhibitory Effects of Statins on Cardiac Hypertrophy and Fibrosis: Novel Mechanism of the Pleiotropic Effects of Statins

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 67; no. 5; pp. 878 - 889
• Main Authors: Kudo, Shun, Satoh, Kimio, Nogi, Masamichi, Suzuki, Kota, Sunamura, Shinichiro, Omura, Junichi, Kikuchi, Nobuhiro, Kurosawa, Ryo, Satoh, Taijyu, Minami, Tatsuro, Ikeda, Shohei, Miyata, Satoshi, Shimokawa, Hiroaki
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.05.2016
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Blotting, Western; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cell Proliferation - drug effects; Cells, Cultured; Chemokines - metabolism; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Disease Models, Animal; Fibrosis - metabolism; Fibrosis - pathology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Mice; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Pravastatin - pharmacology; Random Allocation; Rats; Reactive Oxygen Species - metabolism; Real-Time Polymerase Chain Reaction - methods; Role; Species Specificity; statin; chemokines; angiotensin II; pravastatin; oxidative stress
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.115.07089

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.