Abstract
Advanced glycation end-products (AGEs) are involved in the development of vascular smooth muscle cell (VSMC) dysfunction and the progression of atherosclerosis. However, AGEs may indirectly affect VSMCs via AGEs-induced signal transduction between monocytes and human umbilical endothelial cells (HUVECs), rather than having a direct influence. This study was designed to elucidate the signaling pathway underlying AGEs-RAGE axis influence on VSMC dysfunction using a co-culture system with monocytes, HUVECs and VSMCs. AGEs stimulated production of reactive oxygen species and pro-inflammatory mediators such as tumor necrosis factor-α and interleukin-1β via extracellular-signal-regulated kinases phosphorylation and nuclear factor-κB activation in HUVECs. It was observed that AGEs-induced pro-inflammatory cytokines increase VSMC proliferation, inflammation and vascular remodeling in the co-culture system. This result implies that RAGE plays a role in AGEs-induced VSMC dysfunction. We suggest that the regulation of signal transduction via the AGEs-RAGE axis in the endothelium can be a therapeutic target for preventing atherosclerosis.
Highlights
Advanced glycation end products (AGEs) are formed by non-enzymatic glycation of proteins with other substances, such as carbohydrates or lipids (Basta et al 2004)
Human umbilical endothelial cells were transfected with either non-silencing control siRNA or RAGE-specific siRNA (20 nM), and RAGE expression was assessed by real-time PCR and Western blot analysis at 48 h posttransfection
The results showed that treatment with glycol-AGEs induced a significant increase in ROS generation, which could be inhibited by an addition of apocynin or rotenone
Summary
Advanced glycation end products (AGEs) are formed by non-enzymatic glycation of proteins with other substances, such as carbohydrates or lipids (Basta et al 2004). The interaction of AGEs with their receptor (RAGE) on the cell surface causes upregulation of transcription factors such as nuclear factor (NF)-jB, leading to the expression of various pro-inflammatory cytokines and cell adhesion molecules that cause increased recruitment of monocytes into endothelial cells (ECs). This implies that AGEs-RAGE interactions are key steps in EC dysfunction and atherosclerosis (Davignon & Ganz 2004; Sitia et al 2010; Mudau et al 2012). Those authors provided a special cellular environment (Wu et al 2008), the co-culture system with ECs and VSMCs could not exactly simulate an Supplemental data for this article can be accessed here ß 2016 Informa UK Limited, trading as Taylor & Francis Group
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