Abstract
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.
Highlights
Increasing evidence has indicated that exposure to environmental pollutants such as particulate matter (PM) and ultra-fine particles (UFPs), residual oil fly ash (ROFA), lead to systemic pro-oxidant accumulation and inflammation, both of which play a critical role in the development of cardiopulmonary diseases [1,2], a major health issue worldwide with significant morbidity and mortality [3]
This study showed that the plasma and urinary vanadium concentrations significantly increased in NaVO3-exposed mice (mean 407.5 ± 50.4 nanograms per milliliter (ng/mL) in plasma, (n = 19) and 469 ± 147.4 μg/g creatinine in urine, (n = 10)) as compared to control mice exposed to endotoxin-free water (mean 30.41 ± 1.881 ng/mL in plasma, (n = 6) and 0.69 ± 0.18 μg/g creatinine in urine, (n = 5)) (Figure 1A,B), suggesting that intranasal administered NaVO3 can be absorbed into the circulation system
The decrease in vascular smooth muscle cell (VSMC) differentiation marker proteins such as SM22α in atherosclerotic lesions is a common characteristic of atherosclerosis [3,29], we determined whether intranasal administration of NaVO3 significantly decreased SM22α
Summary
Increasing evidence has indicated that exposure to environmental pollutants such as particulate matter (PM) and ultra-fine particles (UFPs), residual oil fly ash (ROFA), lead to systemic pro-oxidant accumulation and inflammation, both of which play a critical role in the development of cardiopulmonary diseases [1,2], a major health issue worldwide with significant morbidity and mortality [3]. Inhalation of air containing vanadium can lead to pathological effects on human organ systems including the respiratory system, lungs, neurological system, eyes, hematopoietic tissue, immune system, and cardiac physiology, potentially through the induction of reactive oxygen species (ROS) and inflammatory responses [10,11,12]. These inhalations studies with mice have demonstrated that the form of vanadium is critical, with some being much more toxic than others [13,14]
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