Abstract
Statins have been demonstrated to exert pleiotropic anti-atherogenic effects in vascular smooth muscle cells (VSMCs), including inhibition of VSMC migration and proliferation. However, the mechanism underlying this inhibition is not fully understood. A previous microarray study on aortas of statin-treated mice have demonstrated regulator of G-protein signaling 5 (RGS5) to show the greatest increase in expression among non-cytoskeletal proteins. We hypothesized that by inhibiting G-protein signaling involved in VSMC recruitment, RGS5 may contribute to the pleiotropic effects of statins in VSMCs. VSMCs were isolated from mouse aortas and incubated at different concentrations of fluvastatin for 24 hours. Quantitative real-time polymerase chain reaction analysis demonstrated that RGS5 expression significantly increased with 10 μM and 100 μM fluvastatin as compared to vehicle-treated controls (P<0.05), but not with 1 μM fluvastatin. Preliminary time profile studies with 10 μM fluvastatin suggest that the upregulation of RGS5 occurs after 18 hours, which remains stable for up to 48 hours. In order to assess the role of RGS5 during atherosclerosis progression, RGS5/apoE dKO mice, along with RGS5 WT/apoE KO littermate mice were generated and placed on a high cholesterol diet for 12 weeks. During this period, RGS5/apoE dKO mice displayed markedly reduced survival as compared to RGS5 WT/apoE KO mice (P<0.05). Subsequent Oil-Red O stained plaque size analysis in the thoracic aorta demonstrated a larger normalized lesion size in RGS5/apoE dKO mice as compared to littermate RGS5 WT/apoE KO mice (P<0.05). These results suggest an inhibitory role of RGS5 in the progression of atherosclerosis, and that its upregulation in VSMCs following statin treatment may contribute to the therapeutic pleiotropic effects of statins. Future experiments will assess the role of the statin-induced RGS5 upregulation in modulating signaling pathways involved in VSMC recruitment.
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