title: Excess nitric oxide impairs LXR(α)-ABCA1-dependent cholesterol efflux in macrophage foam cells.
abstract: Excess nitric oxide (NO) promotes the progression of atherosclerosis by increasing the oxidation of low-density lipoprotein (LDL) and inflammatory responses. However, little is known about the impact of NO and its underlying molecular mechanism on lipid metabolism of macrophage foam cells. In this study, Oil-red O staining, cholesterol and triglyceride assay, Dil-oxidized LDL (oxLDL) binding assay, cholesterol efflux assay, real-time RT-PCR and Western blot analysis were used for in vitro experiments. Apolipoprotein E-deficient (apoE(-/-) ) and apoE and inducible nitric oxide synthase-deficient (apoE(-/-) iNOS(-/-) ) mice were as our in vivo models. Treatment with S-nitroso-N-acetyl-D,L-penicillamine (SNAP), an NO donor, exacerbated oxLDL-induced cholesterol accumulation in macrophages, because of reduced efficacy of cholesterol efflux. In addition, SNAP decreased the protein level of ATP-binding cassette transporter A1 (ABCA1) without affecting scavenger receptor type A (SR-A), CD36, ABCG1, or SR-B1 levels. This SNAP-mediated downregulation of ABCA1 was mainly through the effect of NO but not peroxynitrite. Furthermore, the SNAP-downregulated ABCA1 was due to the decrease in the liver X receptor α (LXRα)-dependent transcriptional regulation. Moreover, genetic deletion of iNOS increased the serum capacity of reverse cholesterol efflux and protein expression of LXRα, ABCA1, and SR-BI in aortas and retarded atherosclerosis in apoE(-/-) mice. Our findings provide new insights in the pro-atherogenic effect of excess NO on cholesterol metabolism in macrophages.
authors.affiliation: Department of Physiology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Zhao
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
authors.forename: Shing-Jong
authors.initials: SJ
authors.lastname: Lin
authors.forename: Jeng
authors.initials: J
authors.lastname: Wei
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Lee
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced / Q000378:metabolism*; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects*; D008077:Lipoproteins, LDL; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism* / Q000633:toxicity; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis / Q000378:metabolism*; D010084:Oxidation-Reduction; D026423:S-Nitroso-N-Acetylpenicillamine / Q000008:administration & dosage
chemical_list: D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D057093:Orphan Nuclear Receptors; D026423:S-Nitroso-N-Acetylpenicillamine; C577833:Abca1 protein, mouse; C000605214:Nr1h3 protein, mouse; C496317:Nos2 protein, mouse