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Anticoagulant Effects of Synthetic Retinoids Mediated Via Different Receptors on Human Leukemia and Umbilical Vein Endothelial Cells
Misako Shibakura,
Takatoshi Koyama,
Takako Saito,
Koichi Shudo,
Nobuyuki Miyasaka,
Ryuichi Kamiyama, and
Shinsaku Hirosawa
From the School of Allied Health Sciences and the First Department of Internal Medicine, Tokyo Medical and Dental University, and the Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
We recently found that retinoic acids (RAs) exert anticoagulant effects by upregulating thrombomodulin (TM) and downregulating tissue factor (TF ) expression in acute promyelocytic leukemia (APL) cells and monoblastic leukemia cells. Two classes of nuclear RA receptors, termed retinoic acid receptors (RARs) and retinoid X receptors, have been identified. Each receptor class consists of three subtypes. In the present study, we have used several synthetic retinoids to determine which receptor subtypes are involved in the regulation of TM and TF expression in NB4 APL cells, U937 monoblastic leukemia cells, and human umbilical vein endothelial cells (HUVECs). Am80, which has no binding affinity for RAR , and Ch55, which does not bind to cytoplasmic retinoic acid binding protein (CRABP), upregulated TM and downregulated TF in NB4 and U937 cells, similar to all-trans RA (ATRA). A specific RAR antagonist, Ro41-5253, significantly suppressed the upregulation of TM by ATRA and Am80 in NB4 cells, U937 cells, and HUVECs. In contrast, only with preincubation with both RAR and RAR antagonists was downregulation of TF by retinoids suppressed in NB4 cells. These findings indicate that the mechanism of transactivation and transrepression functions of RARs are distinct and also elucidate the major role of RAR in TM upregulation by retinoids in leukemic cells and HUVECs and the cooperation of RAR and RAR in TF downregulation by retinoids. They also indicate that binding to CRABP is not required for the anticoagulant effect of retinoids and that synthetic retinoids will prove very useful in controlling distinct targets, the TM and TF genes, at the level of transcription, and will permit the development of retinoids with a new type of anticoagulant effect.
Blood, Vol. 90 No. 4 (August 15), 1997:
pp. 1545-1551
© 1997 by The American Society of Hematology.
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