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Open AccessArticle

Vanadium Derivative Exposure Promotes Functional Alterations of VSMCs and Consequent Atherosclerosis via ROS/p38/NF-κB-Mediated IL-6 Production

1
Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan
2
Graduate Institutes of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan
3
National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan 35053, Taiwan
4
Graduate Institute of Basic Medical Science, China Medical University Hospital Taichung, Taichung 404, Taiwan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(24), 6115; https://doi.org/10.3390/ijms20246115
Received: 12 November 2019 / Revised: 1 December 2019 / Accepted: 2 December 2019 / Published: 4 December 2019
(This article belongs to the Section Molecular Biology)
Vanadium is a transition metal widely distributed in the Earth’s crust, and is a major contaminant in fossil fuels. Its pathological effect and regulation in atherosclerosis remain unclear. We found that intranasal administration of the vanadium derivative NaVO3 significantly increased plasma and urinary vanadium levels and induced arterial lipid accumulation and atherosclerotic lesions in apolipoprotein E-deficient knockout mice (ApoE−/−) murine aorta compared to those in vehicle-exposed mice. This was accompanied by an increase in plasma reactive oxygen species (ROS) and interleukin 6 (IL-6) levels and a decrease in the vascular smooth muscle cell (VSMC) differentiation marker protein SM22α in the atherosclerotic lesions. Furthermore, exposure to NaVO3 or VOSO4 induced cytosolic ROS generation and IL-6 production in VSMCs and promoted VSMC synthetic differentiation, migration, and proliferation. The anti-oxidant N-acetylcysteine (NAC) not only suppresses IL-6 production and VSMC pathological responses including migration and proliferation but also prevents atherosclerosis in ApoE−/− mice. Inhibition experiments with NAC and pharmacological inhibitors demonstrated that NaVO3-induced IL-6 production is signaled by ROS-triggered p38-mediated NF-κB-dependent pathways. Neutralizing anti-IL-6 antibodies impaired NaVO3-mediated VSMC migration and proliferation. We concluded that NaVO3 exposure activates the ROS-triggering p38 signaling to selectively induce NF-κB-mediated IL-6 production. These signaling pathways induce VSMC synthetic differentiation, migration, and proliferation, leading to lipid accumulation and atherosclerosis.
Keywords: vanadium derivatives; ROS generation; IL-6 production; VSMCs; atherosclerosis vanadium derivatives; ROS generation; IL-6 production; VSMCs; atherosclerosis
MDPI and ACS Style

Yeh, C.-C.; Wu, J.-Y.; Lee, G.-L.; Wen, H.-T.; Lin, P.; Kuo, C.-C. Vanadium Derivative Exposure Promotes Functional Alterations of VSMCs and Consequent Atherosclerosis via ROS/p38/NF-κB-Mediated IL-6 Production. Int. J. Mol. Sci. 2019, 20, 6115.

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