Abstract
Atherosclerosis is a chronic vascular disease caused by inflammation and accumulation of lipids in the blood vessels. Macrophages in atherosclerotic lesions participate in lipid accumulation giving rise to formation of foam cells and production of mediating inflammatory cytokines. This makes them an attractive target for therapy. Previous studies have shown that retinoid signaling plays a broader role in modulating macrophage lipid metabolism and its inflammatory phenotype. Our preliminary results showed that when macrophages (RAW267.4 cells and mouse peritoneal macrophages) were treated with all-trans retinoic acid or retinoic acid receptor alpha (Rarα)-specific agonist, cholesterol efflux genes like Abca1 And Abcg1 and anti-inflammatory gene like Arg-1 were significantly increased. We hypothesized that retinoic acid receptor alpha (Rarα) may play a role in macrophages to protect against diet-induced atherosclerosis. To test this hypothesis, we conducted in-vivo studies using macrophage-specific Rarα knockout mice. Rarα floxed mice were crossed with lysozyme-cre transgenic mice to generate macrophage specific knockout mice (m-Rarα -/- ). Rarα fl/fl (control) and m-Rarα -/- were given high fat/high cholesterol (HFHC) diet for 16 weeks. Intracellular triglyceride and cholesterol levels were significantly increased in peritoneal macrophages of m-Rarα -/- compared to the control. Analysis of macrophage gene expression showed increase in the expression of pro-inflammatory genes (Il-1β, Tnfα and Tgm-2) with decrease in genes involved in cholesterol efflux (Abca1 and Abcg1) and anti-inflammation (Arg-1 and Mrc-1) in m-Rarα -/- macrophages. This implies that loss of Rarα in macrophages can aggravate atherosclerosis. To test this hypothesis, we generated mice deficient in macrophage Rarα and low-density lipoprotein receptor and their control mice. These mice were then fed an HFHC diet for 16 weeks. The Oil Red O staining of aortas showed that mice lacking macrophage Rar had a significant increase in atherosclerotic plaques compared to the control mice. Our data demonstrate that Rarα in macrophages is protective from atherosclerosis.
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