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• W2110247704 abstract "1,25-Dihydroxyvitamin D₃ (1,25D₃) has a potential antiatherosclerotic effect through anti-inflammatory actions. We investigated how 1,25D₃ regulates tumor necrosis factor-<i>α</i> (TNF-<i>α</i>)–induced lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression in cultured human aortic smooth muscle cells. TNF-<i>α</i> activated Rac1/reactive oxygen species/spleen tyrosine kinase and transcriptional factors, activator protein-1, and nuclear factor <i>κ</i>B, which led to LOX-1 expression. 1,25D₃ inhibited TNF-<i>α</i>–induced LOX-1 expression by inhibiting Rac1 activation and thereby its downstream signals. 1,25D₃ rapidly induced extracellular Ca²⁺ influx. Verapamil, an inhibitor of L-type calcium channels, inhibited 1,25D₃-induced Ca²⁺ influx and counteracted the inhibitory effects of 1,25D₃ on Rac1 activation, whereas Bay K8644 [1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid, methyl ester], an L-type calcium channel agonist, attenuated TNF-<i>α</i>–induced Rac1 activation, as 1,25D₃ did. 1,25D₃ induced the ectodomain shedding of TNF receptor 1 (TNFR1), which was abolished by verapamil and in Ca²⁺-free media. Like 1,25D₃, Bay K8644 induced the ectodomain shedding of TNFR1. Both 1,25D₃ and Bay K8644 caused the translocation of a disintegrin and metalloprotease (ADAM) 10 from the cytoplasm to the plasma membrane, which was dependent on extracellular Ca²⁺ influx. In contrast, depletion of ADAM10 by transfection of ADAM10–small interfering RNA prevented 1,25D₃- or Bay K8644–induced ectodomain shedding of TNFR1 and abolished the suppressive effect of 1,25D₃ on TNF-<i>α</i>–induced Rac1 activation. Taken together, these findings suggest that 1,25D₃ induces extracellular Ca²⁺ influx via L-type calcium channel, triggering ADAM10-mediated ectodomain shedding of TNFR1, and it thereby decreases responsiveness to TNF-<i>α</i>. By shedding TNFR1 from the cell surface, 1,25D₃ may regulate inflammation and atherogenesis, whereas this effect could be attenuated by calcium channel blockers." @default.
• W2110247704 created "2016-06-24" @default.
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• W2110247704 date "2015-01-02" @default.
• W2110247704 modified "2023-10-16" @default.
• W2110247704 title "1,25-Dihydroxyvitamin D₃ Causes ADAM10-Dependent Ectodomain Shedding of Tumor Necrosis Factor Receptor 1 in Vascular Smooth Muscle Cells" @default.
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• W2110247704 doi "https://doi.org/10.1124/mol.114.097147" @default.
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