1alpha,25-dihydroxyvitamin D(3) and its potent synthetic analogs downregulate tissue factor and upregulate thrombomodulin expression in monocytic cells, counteracting the effects of tumor necrosis factor and oxidized LDL.
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.


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.
Ohsawa
M
M
School of Allied Health Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Koyama
T
T
Yamamoto
K
K
Hirosawa
S
S
Kamei
S
S
Kamiyama
R
R
D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018180:Thrombomodulin / Q000187:drug effects* / Q000378:metabolism; D013925:Thromboplastin / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D008077:Lipoproteins, LDL; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D013925:Thromboplastin; D002117:Calcitriol; C051883:maxacalcitol