Arsenic exposure is correlated with atherosclerosis in epidemiological studies and in animal models. We have previously shown that arsenic exposure enhanced atherosclerotic plaque size, increased plaque lipid content and decreased plaque smooth muscle cell and collagen contents in apoE-/- mice. However, the percentage of plaque-resident macrophages, the primary drivers of atherosclerosis remained unchanged. Therefore, we hypothesized that while arsenic does not change the quantity of macrophages, it alters macrophage transcriptome towards a pro-atherogenic state. To test this hypothesis, we used bone marrow-derived macrophages, polarized them to either IFN-ɣ stimulated, pro-inflammatory or IL-4 stimulated, alternatively-activated macrophages in the presence or absence of 0.67 µM (50 ppb) arsenic and performed RNA sequencing. Arsenic exposure altered the gene expression of the macrophages in a subtype-specific manner. Most differentially expressed genes (88%) were altered specifically in either IFN-ɣ- or IL-4-stimulated macrophages, while in the remaining 12% genes that changed in both cell types, did so in opposite directions. In IL-4-stimulated macrophages, arsenic significantly downregulated the genes involved in cholesterol biosynthesis and the chemokines, CCL17/CCL22. Whereas, in IFN-ɣ-stimulated macrophages, genes associated with liver X receptor (LXR) pathway were downregulated by arsenic. Using a bone marrow transplant experiment, we validated that deletion of LXRα from the hematopoietic compartment rescued arsenic-enhanced atherosclerosis in apoE-/- mouse model. Together, these data suggest that arsenic modulates subtype-specific transcriptomic changes in macrophages and further emphasize the need to define macrophage heterogeneity in atherosclerotic plaques in order to evaluate pro-atherogenic role of arsenic.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.