Abstract
Advanced glycation endproducts (AGEs)-induced vascular smooth muscle cell (VSMCs) proliferation and formation of reactive oxygen species (ROS) are emerging as one of the important mechanisms of diabetic vasculopathy but little is known about the antioxidative action of HMG CoA reductase inhibitor (statin) on AGEs. We hypothesized that statin might reduce AGEs-induced intracellular ROS of VSMCs and analyzed the possible mechanism of action of statin in AGEs-induced cellular signaling. Aortic smooth muscle cell of Sprague-Dawley rat (RASMC) culture was done using the different levels of AGEs stimulation in the presence or absence of statin. The proliferation of RASMC, ROS formation and cellular signaling was evaluated and neointimal formation after balloon injury in diabetic rats was analyzed. Increasing concentration of AGEs stimulation was associated with increased RASMC proliferation and increased ROS formation and they were decreased with statin in a dose-dependent manner. Increased NF-kappaB p65, phosphorylated ERK, phosphorylated p38 MAPK, cyclooxygenase-2, and c-jun by AGEs stimulation were noted and their expression was inhibited by statin. Neointimal formation after balloon injury was much thicker in diabetic rats than the sham-treated group but less neointimal growth was observed in those treated with statin after balloon injury. Increased ROS formation, subsequent activation of MAPK system and increased VSMC proliferation may be possible mechanisms of diabetic vasculopathy induced by AGEs and statin may play a key role in the treatment of AGEs-induced diabetic atherosclerosis.
Highlights
Recent studies have demonstrated that advanced glycation endproducts (AGEs) and their receptorligand interactions play a key role in neointimal formation after vascular injury, irrespective of diabetes status (Brownlee et al, 1988; Sakaguchi et al, 2003; Stephenson et al, 2003; Zhou et al, 2003)
We provide evidence of the critical involvement of statin in the process of AGEs-induced intracellular Reactive oxygen species (ROS) formation of vascular smooth muscle cell (VSMC)
Recent work has focused on the role of AGEs and receptor for AGE (RAGE) in macro- and microvascular complications in diabetes mellitus (DM), and there are several potential mechanisms by which AGEs may be involved in macrovascular disease (Kanauchi et al, 2001; Rojas and Morales, 2004)
Summary
Recent studies have demonstrated that advanced glycation endproducts (AGEs) and their receptorligand interactions play a key role in neointimal formation after vascular injury, irrespective of diabetes status (Brownlee et al, 1988; Sakaguchi et al, 2003; Stephenson et al, 2003; Zhou et al, 2003). Several reports have suggested that statin could act as an antioxidant in experimental atherosclerosis in animals (Singh et al, 1997; Takemoto et al, 2001; Wassmann et al, 2002), inhibiting oxidation of LDL by activated monocyte-derived macrophages (Giroux et al, 1993). Another recent article revealed that statin inhibited p38 MAPK and inhibited membrane translocation of the small G protein family members (Ras1- and RhoA-) (Senokuchi et al, 2005). Despite the potent impact of statin on atherosclerosis, little is known about the molecular mechanism of statin as antioxidants
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