Vanadium promotes atherosclerosis through induction of VSMC proliferation and migration mediated by p38-mediated ROS-IL-6 production Chang-Ching Yeh1.2., Cheng-Chin Kuo1.2. 1Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan; 2Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan Vanadium is a ubiquitous air pollutant in high concentrations in the earth's crust, ocean, soil, and fossil fuels. Despite substantial evidence supporting the pathogenic correlation of vanadium exposure in the development of cardiopulmonary diseases, its pathological mechanism in the regulation of VSMC function and atherogenesis remains unclear. The aim of this study was to elucidate the mechanism by which vanadium regulates vascular smooth muscle cells (VSMCs) function and atherogenesis. Incubation of VSMCs with different charges of vanadium such as VOSO4 (4+), and NaVO3 (5+) revealed that promoted VSMCs migration and proliferation accompanied by inducing mitochondria superoxide, cytosol reactive oxygen species, and IL-6 but not IL-1β, IL-18 and TNF-α. Importantly, intranasal administration of vanadium in ApoE knockout mice not only induced atheroscleroticplaque formationbut also increased serum ROS level as compared with control mice. In addition, N-acetylcysteine (NAC), a potent antioxidant, significantly reduced the intracellular ROS production, IL-6 production, and VSMCs proliferation and migration induced by vanadium. Neutralizing anti-IL-6 antibodies impaired vanadium-induced IL-6 production but notROSgeneration. Inhibition experiments with pharmacological inhibitors demonstrated that vanadium-induced cytosol ROS and IL-6 production is signaled by p38 kinase-dependent signaling. Taken together, these results suggest vanadium is an atherogenic environmental toxicant and disturbs homeostasis of the vascular microenvironment via p38 kinase mediated production of ROS and IL-6 in VSMCs, thereby promoting VSMCs migration and proliferation.
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