RT Journal Article
SR Electronic
T1 1,25-Dihydroxyvitamin D3 Causes ADAM10-dependent Ectodomain Shedding of TNF Receptor 1 in Vascular Smooth Muscle Cells.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.097147
DO 10.1124/mol.114.097147
A1 Won Seok Yang
A1 Hyun Woo Kim
A1 Joo Mi Lee
A1 Nam Jeong Han
A1 Mee Jeong Lee
A1 Su-Kil Park
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/01/02/mol.114.097147.abstract
AB 1,25-Dihydroxyvitamin D3 (1,25D3) has a potential anti-atherosclerotic effect through anti-inflammatory actions. We investigated how 1,25D3 regulates tumor necrosis factor-α (TNF-α)-induced lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression in cultured human aortic smooth muscle cells. TNF-α activated Rac1/reactive oxygen species/spleen tyrosine kinase and transcriptional factors, activator protein-1 and nuclear factor κB, which led to LOX-1 expression. 1,25D3 inhibited TNF-α-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, an L-type calcium channel agonist, attenuated TNF-α-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-siRNA prevented 1,25D3- or Bay K8644-induced ectodomain shedding of TNFR1 and abolished the suppressive effect of 1,25D3 on TNF-α-induced Rac1 activation. Taken together, the findings suggest that 1,25D3 induces extracellular Ca2+ influx via L-type calcium channel, triggering ADAM10-mediated ectodomain shedding of TNFR1 and, thereby decreases responsiveness to TNF-α. By shedding TNFR1 from the cell surface, 1,25D3 may regulate inflammation and atherogenesis, whereas this effect could be attenuated by calcium channel blockers.