Advanced Oxidation Protein Products Exacerbates Lipid Accumulation and Atherosclerosis Through Downregulation of ATP-Binding Cassette Transporter A1 and G1 Expression in Apolipoprotein E Knockout Mice

Background: Both clinical data and basic science studies suggest that advanced oxidation protein products (AOPPs) may contribute to the progression of atherosclerosis. The aim of this study was to investigate the effects of AOPPs on ATP-binding cassette transporter (ABC) A1 and ABCG1 expression, lipid accumulation and atherosclerotic lesions in apolipoprotein E knockout (apoE-KO) mice. Methods and Results: Male 8-week-old apoE-KO mice were fed a high-fat/high-cholesterol diet. Mice received intraperitoneal injections of AOPPs (5 mg/kg) and/or Janus Kinase (JAK) inhibitor AG-490 (5 mg/kg) once every other day for 8 weeks. As shown in our data, AOPPs increased lipid levels of plasma, and promoted advanced lesions in the aortic regions in apoE-KO mice. The ABCA1, ABCG1 and liver X receptor alpha (LXR alpha) expression were down-regulated in apoE-KO mice treated with AOPPs, whereas the lesions in the aortas were decreased, and the ABCA1, ABCG1 and LXR alpha expression were upregulated in mice treated with AOPPs plus AG-490, compared to the mice treated with AOPPs only. The ABCA1 and LXR alpha expressions of aortas, liver and intestine were downregulated in the AOPPs group, while the expressions were upregulated in the AOPP5-plus-AG-490 group when compared to the AOPPs group. The same results can be also observed in peritoneal macrophages. Conclusions: AOPPs increase accumulation of lipids and exacerbate atherosclerosis through downregulation of ABCA1 and ABCG1 expression, and the JAK-LXR alpha signaling pathway in apoE-KO mice.