Abstract 541: SmgGDS as a Crucial Mediator of the Inhibitory Effects of Statins on Cardiac Hypertrophy and Fibrosis -Novel Mechanism of the Pleiotropic Effects of Statins-
Background: Statins are widely known to exert beneficial pleiotropic effects mediated by anti-oxidative and anti-inflammatory mechanisms, independent of their LDL-cholesterol lowering effect. However, the detailed molecular mechanisms of the pleiotropic effects of statins remain to be fully elucidated. Here, we demonstrate that small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins.
Methods and Results: SmgGDS+/- and wild-type (WT) mice were treated with continuous infusion of angiotensin II (AngII) for 2 weeks with and without oral treatment with atorvastatin (10 mg/kg/day) or pravastatin (50 mg/kg/day). At 2 weeks, the extents of AngII-induced cardiac hypertrophy and fibrosis were comparable between the 2 genotypes. However, statins significantly attenuated cardiomyocyte hypertrophy, fibrosis and left ventricular diastolic dysfunction in WT mice, but not in SmgGDS+/- mice. Since SmgGDS was highly expressed in cardiac fibroblasts (CFs) in the heart, we then examined the role of SmgGDS in cultured CFs from WT and SmgGDS+/- mice. In SmgGDS+/- CFs, Rac1 expression, ERK1/2 activity, Rho-kinase activity and inflammatory cytokines secretion in response to AngII were significantly increased as 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 up-regulations of inflammatory cytokines/chemokines and growth factors in SmgGDS+/- CFs as compared with WT CFs. Importantly, conditioned medium from SmgGDS+/- CFs increased BNP expression in neonatal rat cardiomyocytes to a greater extent than that from WT CFs. Furthermore, atorvastatin significantly increased SmgGDS secretion from mouse and human CFs. Finally, treatment with recombinant SmgGDS significantly reduced Rac1 expression in SmgGDS+/- CFs.
Conclusion: These results indicate that both intracellular and extracellular SmgGDS play a crucial role in the inhibitory effects of statins on cardiac hypertrophy and fibrosis, partly through inhibition of Rac1, Rho-kinase and ERK1/2 pathways, demonstrating the novel mechanism of the pleiotropic effects of statins.
Author Disclosures: S. Kudo: None. K. Satoh: None. M. Nogi: None. K. Suzuki: None. S. Sunamura: None. J. Omura: None. N. Kikuchi: None. R. Kurosawa: None. T. Satoh: None. T. Minami: None. S. Ikeda: None. H. Shimokawa: None.
- © 2015 by American Heart Association, Inc.