Using the Apolipoprotein E Knock-Out Mouse Model to Define Atherosclerotic Plaque Changes Induced by Low Dose Arsenic

Abstract

Arsenic exposure increases the risk of atherosclerosis, the gradual occlusion of the large arteries with fibro-fatty plaque. While epidemiologic data provide convincing evidence this is true at higher exposures, it is unclear whether this may occur at low arsenic exposures, near the maximum contaminant level of 10 ppb. We have previously shown that 200 ppb arsenite in the drinking water increased the atherosclerosis in apolipoprotein E knock-out (apoE-/-) mice after 13 weeks, but the effects of lower concentrations were unknown. Therefore, here, we analyzed the effects of oral exposure to arsenite from 10 to 200 ppb after 13 weeks. Importantly, we found that even at the lowest concentration of arsenite, there was a significant increase in atherosclerotic plaque size. In our previous studies, we found that arsenite exposure resulted in decreased smooth muscle cells (SMCs) and collagen within the plaque. This change is indicative of a less stable phenotype that could increase the risk of rupture and subsequently, myocardial infarct or stroke in humans. In addition, we observed that lipid increased within the plaque without concomitant increase in macrophage content, suggesting that the macrophages were retaining more lipid intracellularly. We also assessed these plaque components in apoE-/- mice exposed to 10-200 ppb arsenite. Interestingly, we observed that macrophage lipid accumulation occurred at lower concentrations than the decreased SMC/collagen content. Together these data suggest that in the apoE-/- model, low arsenite concentrations are pro-atherogenic and that macrophage lipid homeostasis is more sensitive to arsenite-induced perturbation than the SMCs.