| First Author | Lemaire M | Year | 2014 |
| Journal | Toxicol Sci | Volume | 142 |
| Issue | 2 | Pages | 477-88 |
| PubMed ID | 25273567 | Mgi Jnum | J:227826 |
| Mgi Id | MGI:5702846 | Doi | 10.1093/toxsci/kfu197 |
| Citation | Lemaire M, et al. (2014) Genetic deletion of LXRalpha prevents arsenic-enhanced atherosclerosis, but not arsenic-altered plaque composition. Toxicol Sci 142(2):477-88 |
| abstractText | Arsenic exposure has been linked to an increased incidence of atherosclerosis. Previously, we have shown in vitro and in vivo that arsenic inhibits transcriptional activation of the liver X receptors (LXRs), key regulators of lipid homeostasis. Therefore, we evaluated the role of LXRalpha in arsenic-induced atherosclerosis using the apoE(-/-) mouse model. Indeed, deletion of LXRalpha protected apoE(-/-) mice against the proatherogenic effects of arsenic. We have previously shown that arsenic changes the plaque composition in apoE(-/-) mice. Arsenic decreased collagen content in the apoE(-/-) model, and we have observed the same diminution in LXRalpha(-/-)apoE(-/-) mice. However, the collagen-producing smooth muscle cells (SMCs) were decreased in apoE(-/-), but increased in LXRalpha(-/-)apoE(-/-). Although transcriptional activation of collagen remained the same in SMC from both genotypes, arsenic-exposed LXRalpha(-/-)apoE(-/-) plaques had increased matrix metalloproteinase activity compared with both control LXRalpha(-/-)apoE(-/-) and apoE(-/-), which could be responsible for both the decrease in plaque collagen and the SMC invasion. In addition, arsenic increased plaque lipid accumulation in both genotypes. However, macrophages, the cells known to retain lipid within the plaque, were unchanged in arsenic-exposed apoE(-/-) mice, but decreased in LXRalpha(-/-)apoE(-/-). We confirmed in vitro that these cells retained more lipid following arsenic exposure and are more sensitive to apoptosis than apoE(-/-). Mice lacking LXRalpha are resistant to arsenic-enhanced atherosclerosis, but arsenic-exposed LXRalpha(-/-)apoE(-/-) mice still present a different plaque composition pattern than the arsenic-exposed apoE(-/-) mice. |
