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(Circulation. 2000;102:2867.)
© 2000 American Heart Association, Inc.

Basic Science Reports

1,25-Dihydroxyvitamin D₃ 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

Mai Ohsawa, MS; Takatoshi Koyama, MD; Keiko Yamamoto, PhD; Shinsaku Hirosawa, MD; Sachiko Kamei, MD; Ryuichi Kamiyama, MD

From the School of Allied Health Sciences (M.O., T.K., S.K., R.K.), Institute for Biomaterials and Bioengineering (K.Y.), and First Department of Internal Medicine (S.H.), Tokyo Medical and Dental University, Tokyo, Japan.

Correspondence to Takatoshi Koyama, MD, School of Allied Health Sciences, Faculty of Medicine, Tokyo Medical and Dental University 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail int1koya.mtec{at}med.tmd.ac.jp

Background—We have recently found that a hormonally active form of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], 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)₂D₃ 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)₂D₃ and its potent synthetic analogs (22R)-22-methyl-20-epi-1,25(OH)₂D₃ (KY3) and 22-oxacalcitriol on TF and TM antigen levels, cell surface activities, and mRNA levels in monocytic cells were examined. 1,25(OH)₂D₃ 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)₂D₃ analogs is also mediated by vitamin D receptor. The 1,25(OH)₂D₃ 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.

Key Words: anticoagulants • coagulation • thrombosis

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