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  • Title: The detrimental effect of asymmetric dimethylarginine on cholesterol efflux of macrophage foam cells: Role of the NOX/ROS signaling.
    Author: Chen CH, Zhao JF, Hsu CP, Kou YR, Lu TM, Lee TS.
    Journal: Free Radic Biol Med; 2019 Nov 01; 143():354-365. PubMed ID: 31437479.
    Abstract:
    BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor and has been proposed to be an independent risk factor for cardiovascular diseases. However, little is known about its role in the regulation of lipid metabolism. In this study, we investigated the effect of ADMA on cholesterol metabolism and its underlying molecular mechanism. METHODS: Oxidized low-density lipoprotein (oxLDL)-induced macrophage foam cells were used as an in vitro model. Apolipoprotein E-deficient (apoE-/-) hyperlipidemic mice were used as an in vivo model. Western blot analysis was used to evaluate protein expression. Luciferase reporter assays were used to assess the activity of promoters and transcription factors. Conventional assay kits were used to measure the levels of ADMA, cholesterol, triglycerides, and cytokines. RESULTS: Treatment with oxLDL decreased the protein expression of dimethylarginine dimethylaminohydrolase-2 (DDAH-2) but not DDAH-1. Incubation with ADMA markedly increased oxLDL-induced lipid accumulation in macrophages. ADMA impaired cholesterol efflux following oxLDL challenge and downregulated the expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 by interfering with liver X receptor α (LXRα) expression and activity. Additionally, this inhibitory effect of ADMA on cholesterol metabolism was mediated through the activation of the NADPH oxidase/reactive oxygen species pathway. In vivo experiments revealed that chronic administration of ADMA for 4 weeks exacerbated systemic inflammation, decreased the aortic protein levels of ABCA1 and ABCG1, and impaired the capacity of reverse cholesterol transport, ultimately, leading to the progression of atherosclerosis in apoE-/- mice. CONCLUSION: Our findings suggest that the ADMA/DDAH-2 axis plays a crucial role in regulating cholesterol metabolism in macrophage foam cells and atherosclerotic progression.
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