Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Division of Experimental Medicine, Montreal, Quebec, Canada.
Toxicol Sci. 2018 Nov 1;166(1):213-218. doi: 10.1093/toxsci/kfy201.
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.
砷暴露会增加动脉粥样硬化的风险，即大动脉硬化逐渐被纤维脂肪斑块所阻塞。虽然流行病学数据提供了确凿的证据表明，在较高的暴露水平下确实如此，但目前尚不清楚在接近 10 ppb 的最大污染物水平的低砷暴露下是否会发生这种情况。我们之前已经表明，饮用水中 200 ppb 的亚砷酸盐会在 13 周后增加载脂蛋白 E 敲除（apoE-/-）小鼠的动脉粥样硬化，但尚不清楚较低浓度的亚砷酸盐会产生什么影响。因此，在这里，我们分析了在 13 周后口服接触 10 至 200 ppb 的亚砷酸盐的影响。重要的是，我们发现，即使在亚砷酸盐的最低浓度下，动脉粥样硬化斑块的大小也会显著增加。在我们之前的研究中，我们发现亚砷酸盐暴露会导致斑块内的平滑肌细胞（SMCs）和胶原蛋白减少。这种变化表明斑块的表型更不稳定，这可能会增加破裂的风险，并随后导致人类心肌梗死或中风。此外，我们观察到，斑块内的脂质增加，但巨噬细胞含量没有相应增加，这表明巨噬细胞在细胞内保留了更多的脂质。我们还评估了暴露于 10-200 ppb 亚砷酸盐的 apoE-/-小鼠的这些斑块成分。有趣的是，我们观察到巨噬细胞脂质积累发生在较低浓度，而 SMC/胶原蛋白含量减少。这些数据表明，在 apoE-/-模型中，低浓度的亚砷酸盐具有促动脉粥样硬化作用，并且巨噬细胞脂质稳态对亚砷酸盐诱导的干扰比 SMCs 更敏感。
