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

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 NaVO ₃ 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 NaVO ₃ or VOSO ₄ 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 NaVO ₃ -induced IL-6 production is signaled by ROS-triggered p38-mediated NF-κB-dependent pathways. Neutralizing anti-IL-6 antibodies impaired NaVO ₃ -mediated VSMC migration and proliferation. We concluded that NaVO ₃ 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.
Competing Interests: The authors declare no conflict of interest.