Ps-bpb04-1: dna-aptamer raised against receptor for advanced glycation end products inhibits atherosclerosis

Background and Aims: Interaction of advanced glycation end products (AGEs) with the receptor RAGE could accelerate atherosclerotic plaque formation. However, effect of DNA-aptamer raised against RAGE on atherosclerosis remains unclear. In this study, we aimed to elucidate whether and how RAGE-aptamer could inhibit atherosclrotic lesions and oxidized-LDL uptake of macrophages derived from apolipoprotein E (ApoE)-null mice, a representative animal model of atherosclerosis. We also examined whether RAGE-aptamer could inhibit oxidized-LDL uptake in AGE-exposed mouse peripheral macrophages and human U937 cells. Materials and Methods: Seventeen-week-old male ApoE-null mice were subcutaneously infused with RAGE-aptamer (10 pmoL/g/day) or control-aptamer by osmotic pump for 4 weeks. Peritoneal macrophages were extracted from mice at 21 weeks of age just after intraperitoneal injection of thioglycollate broth. The entire aortae and cross-sections of the aortic roots were stained with Oil Red O or MOMA-2 for the assessment of atherosclerotic lesions or macrophage infiltration. Mouse macrophages and human U937 cells were incubated with 100 μg/mL AGE-bovine serum albumin (AGE-BSA) or non-glycated BSA for 24 hours. Then the cells were treated with RAGE-aptamer or control-aptamer for 18 hours. Oxidized-LDL uptake was determined by Dil-oxidized-LDL fluorescent intensity using immunohistochemistry. Quantitative RT-PCR analysis was performed using TaqMan-based probes and SYBR-based primers. Results: Atherosclerotic lesions and infiltration of macrophages in the aortae isolated from ApoE-null mice infused subcutaneously with RAGE-aptamer were significantly suppressed compared with control-aptamer-treated mice. Oxidized-LDL uptake, and cyclin-dependent kinase 5 (Cdk5) and CD36 gene expression in macrophages extracted from ApoE-null mice infused with RAGE-aptamer were attenuated in comparison to those from mice infused with control-aptamer. Furthermore, RAGE-aptamer significantly inhibited oxidized-LDL uptake, and Cdk5 and CD36 gene expression in mouse macrophages and human U937 cells compared with those exposed with control-aptamer. Gene expression level of Cdk5 in mouse or human U937 cells was correlated with that of CD36. Conclusion: Our present findings suggest that RAGE-aptamer could play a protective role against atherosclerosis through the inhibition of macrophage foam cell formation via Cdk5-CD36 pathway in mice and human, which may be caused by attenuating the harmful effects of AGEs.