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

Sex-Specific Effects of Prenatal and Early Life Inorganic and Methylated Arsenic Exposure on Atherosclerotic Plaque Development and Composition in Adult ApoE−/− Mice

“…ApoE −= − mating pairs were exposed to either tap water or tap water containing 200 ppb arsenic in the form of m-NaAsO 2 (0:35 mg=L NaAsO 2 ; Sigma-Aldrich), disodium methyl arsonate hexahydrate (MMA V ; 0:78 mg=L; Chem Service), cacodylic acid (DMA V ; 0:43 mg=L; Sigma-Aldrich) or monomethylarsonous acid [MMA III ; 0:37 mg=L]. This is a concentration at which we have observed maximal pro-atherogenic effects postnatally (Lemaire et al 2011;Makhani et al 2018). This level of arsenic has been found in the drinking water in highly contaminated areas of Bangladesh (BGS 2000), Argentina (Pérez-Carrera and Fernández Cirelli 2010;Concha et al 1998), and the United States (Neilsen et al 2010).…”

“…Atherosclerotic lesion characterization. The characterization of the atherosclerotic lesions was performed as previously described (Lemaire et al 2014(Lemaire et al , 2011Makhani et al 2018;Negro Silva et al 2017). Briefly, the fixed aorta was rinsed with ultra-pure water, then cut longitudinally and stained en face with oil red O (Electronic Microscopy Sciences), which stains neutral triglycerides and lipids.…”

“…Animal experiments have provided mechanistic insight into the underlying mechanisms of arsenic-enhanced atherosclerosis. We previously showed that postnatal exposure to low (10-50 ppb)-tomoderate (100-200 ppb) concentrations of arsenic as sodium arsenite (NaAsO 2 ) (Lemaire et al 2011;Makhani et al 2018) or methylated arsenicals (Negro Silva et al 2017) resulted in larger atherosclerotic plaques in 18-wk-old male apoE −= − mice. Our data also indicated that arsenic trioxide enhanced lipid accumulation in macrophages (Padovani et al 2010) and increased the attachment of macrophages to the arterial endothelial cell layer in vitro (Lemaire et al 2015).…”

Arsenite inhibits gene expression of perlecan, syndecan-1, -2, -3 and biglycan in cultured vascular endothelial cells

“…Epidemiological studies have shown that arsenic is a possible risk factor for vascular diseases related to atherosclerosis and blood circulation disorder (Moon et al, 2013;Tseng et al, 1995;Chen et al, 1988). It has been also demonstrated that exposure to several arsenic compounds, including arsenite, accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice, a model of human atherosclerosis (Simeonova et al, 2003;Srivastava et al, 2009;Negro Silva et al, 2017;Makhani et al, 2018). Atherosclerosis is initiated by functional damages in vascular endothelial cells followed by monocyte/macrophage invasion into under the endothelium tissue and vascular smooth muscle cell transformation and hyperplasia in the intima of the vascular wall (Ross, 1993).…”

Serum Proteomic Profiling Analysis of Rats Chronically Exposed to Arsenic

“…In the apolipoprotein E knock-out model, As exposure was more pro-atherogenic, even at low concentrations, and As made lipid homeostasis more vulnerable to arsenite-induced perturbation in macrophages. This could increase the risk of rupture and myocardial infarction or stroke in humans [39]. In another study, workers exposed to As had Apo-B and Apo-B/Apo-A1 ratios that were significantly higher and the Apo-A1 was significantly lower than in the control subjects, which shows the influence of As on apolipoproteins, suggesting a potential increased risk of As-related diseases [40].…”