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. Treatment with S‐nitroso‐N‐acetyl‐D,L‐penicillamine (SNAP), an NO donor, exacerbated oxidized LDL (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 inducible NOS increased the serum capacity of reverse cholesterol efflux and protein expression of LXRα, ABCA1 and SR‐BI in aortas and retarded atherosclerosis in apolipoprotein E‐deficient mice. Our findings provide new insights in the pro‐atherogenic effect of excess NO on cholesterol metabolism in macrophages.
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