BACKGROUND: We have recently found that a hormonally active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], exerts anticoagulant effects by upregulating the expression of an anticoagulant glycoprotein, thrombomodulin (TM), and downregulating the expression of a critical coagulation factor, tissue factor (TF), in monocytic cells including human peripheral monocytes. In this study, we investigated the counteracting effects of 1,25(OH)(2)D(3) and its potent analogs on TF induction and TM downregulation by tumor necrosis factor and oxidized LDL in monocytic cells and the modulatory effects of potent analogs on TF and TM expression. METHODS AND RESULTS: Effects of 1,25(OH)(2)D(3) and its potent synthetic analogs (22R)-22-methyl-20-epi-1,25(OH)(2)D(3) (KY3) and 22-oxacalcitriol on TF and TM antigen levels, cell surface activities, and mRNA levels in monocytic cells were examined. 1, 25(OH)(2)D(3) and its potent analogs showed anticoagulant effects in monocytic cells by downregulating TF and upregulating TM expression, counteracting the effects of tumor necrosis factor and oxidized LDL. KY3 was most potent in its regulatory effect on TF and TM expression. CONCLUSIONS: Because KY3 has the highest affinity for vitamin D receptor, our findings suggest that TF and TM regulation by 1, 25(OH)(2)D(3) analogs is also mediated by vitamin D receptor. The 1, 25(OH)(2)D(3) analogs KY3 and 22-oxacalcitriol may have the potential to serve as an agent for preventing and treating atherosclerotic and other cytokine-mediated thrombotic diseases and as a tool for studying the molecular mechanisms of TF and TM regulation.
BACKGROUND: We have recently found that a hormonally active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], exerts anticoagulant effects by upregulating the expression of an anticoagulant glycoprotein, thrombomodulin (TM), and downregulating the expression of a critical coagulation factor, tissue factor (TF), in monocytic cells including human peripheral monocytes. In this study, we investigated the counteracting effects of 1,25(OH)(2)D(3) and its potent analogs on TF induction and TM downregulation by tumor necrosis factor and oxidized LDL in monocytic cells and the modulatory effects of potent analogs on TF and TM expression. METHODS AND RESULTS: Effects of 1,25(OH)(2)D(3) and its potent synthetic analogs (22R)-22-methyl-20-epi-1,25(OH)(2)D(3) (KY3) and 22-oxacalcitriol on TF and TM antigen levels, cell surface activities, and mRNA levels in monocytic cells were examined. 1, 25(OH)(2)D(3) and its potent analogs showed anticoagulant effects in monocytic cells by downregulating TF and upregulating TM expression, counteracting the effects of tumor necrosis factor and oxidized LDL. KY3 was most potent in its regulatory effect on TF and TM expression. CONCLUSIONS: Because KY3 has the highest affinity for vitamin D receptor, our findings suggest that TF and TM regulation by 1, 25(OH)(2)D(3) analogs is also mediated by vitamin D receptor. The 1, 25(OH)(2)D(3) analogs KY3 and 22-oxacalcitriol may have the potential to serve as an agent for preventing and treating atherosclerotic and other cytokine-mediated thrombotic diseases and as a tool for studying the molecular mechanisms of TF and TM regulation.
Authors: W Messenger; C M Nielson; H Li; T Beer; E Barrett-Connor; K Stone; J Shannon Journal: Nutr Metab Cardiovasc Dis Date: 2011-04-03 Impact factor: 4.222
Authors: Jorge N Artaza; Sandra Contreras; Leah A Garcia; Rajnish Mehrotra; Gary Gibbons; Ralph Shohet; David Martins; Keith C Norris Journal: J Health Care Poor Underserved Date: 2011
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Authors: Anastassios G Pittas; Mei Chung; Thomas Trikalinos; Joanna Mitri; Michael Brendel; Kamal Patel; Alice H Lichtenstein; Joseph Lau; Ethan M Balk Journal: Ann Intern Med Date: 2010-03-02 Impact factor: 25.391