Crucial Role of SmgGDS in the Inhibitory Effects of Statins on Cardiac Hypertrophy and Fibrosis in Mice

Introduction: We have previously demonstrated that small GTP-binding protein dissociation stimulator (SmgGDS) plays a crucial role in the pleiotropic effects of HMG-CoA reductase inhibitors (statins) in mice and humans. In the present study, we tested our hypothesis that SmgGDS plays a crucial role in the inhibitory effects of statins on the development of cardiac hypertrophy and fibrosis. Methods & Results: We administered angiotensin II (AngII, 2 mg/kg/day, 2 weeks) to SmgGDS-deficient ( SmgGDS +/- ) mice and littermate controls ( SmgGDS +/+ ), which were orally treated with either statins (atorvastatin 10 mg/kg/day or pravastatin 50 mg/kg/day, n=10 each group) or vehicle. AngII equally elevated systolic blood pressure and promoted cardiac hypertrophy and fibrosis in SmgGDS +/+ and SmgGDS +/- . Both statins significantly reduced LV wall thickness, cardiac myocyte cross-sectional area, and fibrotic area in AngII-infused SmgGDS +/+ mice (all P<0.01). In contrast, the inhibitory effects of statins were absent in AngII-infused SmgGDS +/- mice. Additionally, statins significantly improved LV diastolic function (E/A) in SmgGDS +/+ mice (P<0.01) but not in SmgGDS +/- mice. Interestingly, immunostaining revealed that SmgGDS was highly expressed in cardiac fibroblasts (CFs) in the heart of AngII-infused SmgGDS +/+ mice. Then, we harvested CFs from SmgGDS +/+ and SmgGDS +/- mice and stimulated them with AngII with or without statins. At baseline, SmgGDS +/- CFs showed significant increase in Rac1 expression (1.8-fold), ERK1/2 activity (4.0-fold), Rho-kinase activity (phospho-MYPT/total-MYPT, 1.4-fold) compared to SmgGDS +/+ CFs, whereas Akt activity was significantly less in SmgGDS +/- CFs compared to SmgGDS +/+ CFs (n=4, all P<0.05). Statin treatment significantly reduced Rac1 expression in SmgGDS +/+ CFs (-30%, n=4, P<0.05), which was not observed in SmgGDS +/- CFs, suggesting that SmgGDS mediates the inhibitory effects of statins on Rac1 signaling. Conclusions: These results indicate that SmgGDS plays 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.