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

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.

Restoration of 5-methoxytryptophan protects against atherosclerotic chondrogenesis and calcification in ApoE−/− mice fed high fat diet

“…OPG is an extracellular decoy receptor of RANKL and plays an important role in controlling RANK-mediated osteochondrogenic differentiation and calcification at the basal state [ 29 ]. By contrast, IL-6 drives SMC migration and promotes SMC chondrogenic differentiation and calcification [ 10 , 11 , 30 , 31 ]. Thus by upregulating IL-6 expression on one hand and suppressing OPG on the others TLR2 activation induces osteochondrogenesis and calcification.…”

Involvement of glutathione peroxidases in the occurrence and development of breast cancers

“…It is accepted that an excessive burden of ROS may lead to abnormal cell growth, corresponding changes in intracellular homeostasis and damage to important components of in the cell when the antioxidant defense and/ or DNA repair mechanisms cannot balance the excess oxidants [29]. Oxidative stress, which results from the imbalance between the production and neutralization of ROS, is also reported to be involved in a large number of pathological states, such as Alzheimer's disease [30], Parkinson's disease [31], atherosclerosis [32], heart failure [33], myocardial infarction [34], and hepatic encephalopathy [35]. Importantly, oxidative damage caused by the production of ROS has been linked to the etiology of different types of human cancer [23,36].…”

miR‐141‐5p suppresses vascular smooth muscle cell inflammation, proliferation, and migration via inhibiting the HMGB1/NF‐κB pathway

“…[ 16,31 ] The activation of NF‐κB can also promote the production of IL‐6, and this process induces the differentiation, migration, and proliferation of VSMCs, leading to lipid accumulation and the formation of AS plaque. [ 32 ] In the present work, we demonstrated that the activation of NF‐κB was modulated by miR‐141‐5p inhibitors. Further experiments found that JSH‐23, an NF‐κB nuclear translocation inhibitor, played a similar role in VSMCs as miR‐141‐5p mimics.…”