Chronic Cadmium Exposure Accelerates the Development of Atherosclerosis and Induces Vascular Dysfunction in the Aorta of ApoE−/− Mice
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Cadmium exposure is related to cardiovascular diseases, including hypertension, atherosclerosis, increased oxidative stress, endothelial dysfunction, and specific biochemical changes induced by this metal. Thus, we aimed to investigate whether cadmium exposure induces endothelial dysfunction, accelerates atherosclerotic plaque formation in the aorta, and enhances oxidative stress in apolipoprotein E knockout (ApoE−/−) mice. Experiments were performed in 14-week-old male wild-type and ApoE−/− mice. ApoE−/− mice received cadmium (CdCl2 100 mg/L in drinking water for 28 days) or vehicle (distilled water). After treatment, vascular reactivity to phenylephrine, acetylcholine, and sodium nitroprusside was analyzed using isolated aorta. Bone marrow cells were isolated to assess the production of nitric oxide and reactive oxygen and nitrogen species. ApoE−/− cadmium-treated mice had higher cholesterol levels than non-exposed mice. Cadmium exposure decreased the vasodilatation response to acetylcholine in aortic ring of ApoE−/− mice, though no changes in phenylephrine or sodium nitroprusside responses were observed. l-NAME reduced vasodilator responses to acetylcholine; this effect was lower in ApoE−/− cadmium-treated mice, suggesting reduction in nitric oxide (NO) bioavailability. Moreover, in bone marrow cells, cadmium decreased cytoplasmic levels of NO and increased superoxide anions, hydrogen peroxide, and peroxynitrite in ApoE−/− mice. Morphological analysis showed that cadmium exposure increased plaque deposition in the aorta by approximately 3-fold. Our results suggest that cadmium exposure induces endothelial dysfunction in ApoE−/− mice. Moreover, cadmium increased total cholesterol levels, which may promote the early development of atherosclerosis in the aorta of ApoE−/− mice. Our findings support the hypothesis that cadmium exposure might increase the risk of atherosclerosis.
KeywordsCadmium Atherosclerosis Endothelial dysfunction Oxidative stress
This study was supported by grants from CNPq (nos. 303390/2015-8 and 457897/2014-7), CAPES, and FAPES (nos. 03/2016; 239/2016 and 88/2017).
Compliance with Ethical Standards
All experimental procedures were performed in accordance with the guidelines for the care and handling of laboratory animals as recommended by the National Institutes of Health (NIH), and the study protocols were previously approved by the Ethics Committee of the Federal University of Espirito Santo (071/2016 CEUA-UFES).
Conflict of Interest
The authors declare that they have no conflicts of interest.
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