Abstract 1038: Possible Role of HMG CoA Reductase Inhibitor on the Oxidative Stress induced by Advanced Glycation Endproducts(AGEs) in Vascular Smooth Muscle Cell(VSMC) of Diabetic Vasculopathy
Backgrounds: Advanced glycation endproducts (AGEs) induced smooth muscle cell proliferation and formation of reactive oxygen species(ROS) are emerging as one of the important mechanism of diabetic vasculopathy, but little is known about antioxidative action of HMG CoA Reductase Inhibitor(statins) on AGEs. We hypothesized that statins may reduce the AGEs-induced increased intracellular oxidative stress in VSMCs.
Methods: Rat aortic smooth muscle cell culture was done using the different levels of AGEs (advanced human glycated albumin, Sigma aldrich Chemical) stimulation in the presence or absence of statin. Cell proliferation was measured using the MTT colorimetric assay (Sigma). AGE stimulated RASMC was incubated with 0, 1 and 10 μM of activated statin for 1h and followed by quantitative analysis of the cell proliferation with MTT assay. The activity of ERKs, phosphorylated ERKs, p38, phosphorylated p38, COX-2, c-jun, NFκB and the formation of ROS were evaluated by immunoblotting technique and H2DCFDA reagent, respectively. Carotid balloon injury was also performed in OLETF diabetic rats that were pretreated for 1 week with statins.
Results: Increasing concentration of AGEs stimulation was associated with increased ROS formation, VSMC proliferation and cellular signaling. Compared with the control, statin inhibited AGE-stimulated VSMC proliferation and the activity of ROS-induced cellular signaling by dose dependent manner. Neointimal formation after balloon injury was much less in statin-treated OLEFT rats than in sham-treated group. siRNA-mediated silencing of RAGE (receptor for AGE) expression had no effect on the change of cellular signalling mediated by statins.
Conclusions: In vitro and in vivo data suggest that AGEs play a key role in VSMC proliferation and increase the oxidative stress. Statin inhibits the AGE-induced proliferation of VSMCs and suppresses the cellular signaling activity increased by the ROS formation. Increased ROS formation and activation of MAPK system may be the possible mechanism of AGEs induced vasculopathy and HMG-CoA Reductase Inhibitor may play a role in AGEs induced diabetic atherosclerosis.