TY - JOUR
T1 - The detrimental effect of asymmetric dimethylarginine on cholesterol efflux of macrophage foam cells
T2 - Role of the NOX/ROS signaling
AU - Chen, Chia-Hui
AU - Zhao, Jin-Feng
AU - Hsu, Chiao-Po
AU - Kou, Yu Ru
AU - Lu, Tse-Min
AU - Lee, Tzong-Shyuan
N1 - This study was supported by grants from the Ministry of Science and Technology of Taiwan (105-2320-B-010-036, 105-2811-B-010-022, 106-2320-B-002-057-MY3, 106-2320-B-002-056, and 106-2811-B-002-146).
Copyright © 2019. Published by Elsevier Inc.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
KW - ATP-Binding cassette transporter
KW - Asymmetric dimethylarginine
KW - Atherosclerosis
KW - Cholesterol metabolism
KW - Liver X receptor α
KW - Macrophage foam cell
UR - http://www.scopus.com/inward/record.url?scp=85071375700&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2019.08.016
DO - 10.1016/j.freeradbiomed.2019.08.016
M3 - Article
C2 - 31437479
SN - 0891-5849
VL - 143
SP - 354
EP - 365
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -
