Cilostazol inhibits hyperglucose-induced vascular smooth muscle cell dysfunction by modulating the RAGE/ERK/NF-κB signaling pathways

Background Increasing evidence suggests that high glucose (HG) causes abnormalities in endothelial and vascular smooth muscle cell function (VSMC) and contributes to atherosclerosis. Receptor for advanced glycation end-products (RAGE) has been linked to the pathogenesis of both the macrovascular and microvascular complications of diabetes. Cilostazol is used to treat diabetic vasculopathy by ameliorating HG-induced vascular dysfunction. Objectives In this study, we investigated whether the cilostazol suppression of HG-induced VSMC dysfunction is through RAGE signaling and its possible regulation mechanism. Method We investigated the effect of HG and cilostazol on RAGE signaling in A7r5 rat VSMCs. Aortic tissues of streptozotocin (STZ) diabetic mice were also collected. Results Aortic tissue samples from the diabetic mice exhibited a significantly decreased RAGE expression after cilostazol treatment. HG increased RAGE, focal adhesion kinase (FAK), matrix metalloproteinase-2 (MMP-2), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions, and was accompanied with increased reactive oxygen species (ROS), cell proliferation, adhesion and migration. Cilostazol significantly reversed HG-induced RAGE, ROS, downstream gene expressions and cell functions. RAGE knockdown significantly reversed the expressions of HG-induced vasculopathy related gene expressions and cell functions. Cilostazol with RAGE knockdown had additive effects on downstream ERK/NF-kappa B signaling pathways, gene expressions and cell functions of A7r5 rat VSMCs in HG culture. Conclusions Both in vitro and in vivo experimental diabetes models showed novel signal transduction of cilostazol-mediated protection against HG-related VSMC dysfunction, and highlighted the involvement of RAGE signaling and downstream pathways.