title: Advanced glycation endproducts induce apoptosis of endothelial progenitor cells by activating receptor RAGE and NADPH oxidase/JNK signaling axis.
abstract: Elevated levels of advanced glycation endproducts (AGEs) is an important risk factor for atherosclerosis. Dysfunction of endothelial progenitor cells (EPCs), which is essential for re-endothelialization and neovascularization, is a hallmark of atherosclerosis. However, it remains unclear whether and how AGEs acts on EPCs to promote pathogenesis of atherosclerosis. In this study, EPCs were exposed to different concentrations of AGEs. The expression of NADPH and Rac1 was measured to investigate the involvement of NADPH oxidase pathway. ROS was examined to indicate the level of oxidative stress in EPCs. Total JNK and p-JNK were determined by Western blotting. Cell apoptosis was evaluated by both TUNEL staining and flow cytometry. Cell proliferation was measured by (3)H thymidine uptake. The results showed that treatment of EPCs with AGEs increased the levels of ROS in EPCs. Mechanistically, AGEs increased the activity of NADPH oxidase and the expression of Rac1, a major component of NADPH. Importantly, treatment of EPCs with AGEs activated the JNK signaling pathway, which was closely associated with cell apoptosis and inhibition of proliferation. Our results suggest that the RAGE activation by AGEs in EPCs upregulates intracellular ROS levels, which contributes to increased activity of NADPH oxidase and expression of Rac1, thus promoting cellular apoptosis and inhibiting proliferation. Mechanistically, AGEs binding to the receptor RAGE in EPCs is associated with hyperactivity of JNK signaling pathway, which is downstream of ROS. Our findings suggest that dysregulation of the AGEs/RAGE axis in EPCs may promote atherosclerosis and identify the NADPH/ROS/JNK signaling axis as a potential target for therapeutic intervention.
authors.affiliation: Institute of Cardiovascular Research of PLA, Department of Cardiology, Xinqiao Hospital, The Third Military Medical University Chongqing 400037, China.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Cardiovascular Research of PLA, Department of Cardiology, Xinqiao Hospital, The Third Military Medical University Chongqing 400037, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Jing
authors.affiliation: Institute of Cardiovascular Research of PLA, Department of Cardiology, Xinqiao Hospital, The Third Military Medical University Chongqing 400037, China.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Yu
authors.affiliation: Institute of Cardiovascular Research of PLA, Department of Cardiology, Xinqiao Hospital, The Third Military Medical University Chongqing 400037, China.
authors.forename: Minbao
authors.initials: M
authors.lastname: Song
authors.affiliation: Institute of Cardiovascular Research of PLA, Department of Cardiology, Xinqiao Hospital, The Third Military Medical University Chongqing 400037, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Tan
authors.affiliation: Institute of Cardiovascular Research of PLA, Department of Cardiology, Xinqiao Hospital, The Third Military Medical University Chongqing 400037, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Cui
authors.affiliation: Institute of Cardiovascular Research of PLA, Department of Cardiology, Xinqiao Hospital, The Third Military Medical University Chongqing 400037, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
keywords: Advanced glycation endproducts; JNK pathway; NADPH oxidase; apoptosis; endothelial progenitor cells