Anticoagulant effects of synthetic retinoids and activated vitamin D3.

Abstract

We have recently found that retinoic acids (RAs) evoke an anticoagulant effect by upregulating thrombomodulin (TM) and downregulating expression of tissue factor (TF) in acute promyelocytic leukemia (APL) and monoblastic leukemia cells. Two classes of nuclear RA receptors, termed retinoic acid receptors (RARs) and retinoid X receptors, have already been identified. Each receptor class consists of three subtypes. We have used several synthetic retinoids to find which receptor subtypes are involved in the regulation of TM and TF expression in APL cells NB4, monoblastic leukemia cells U937, and human umbilical vein endothelial cells (HUVECs). Am80, which does not have a binding affinity to RARgamma; Ch55, which does not bind to cytoplasmic retinoic acid-binding protein (CRABP); and a specific RARalpha agonist, Ro40-6055, have been shown to upregulate TM and downregulate TF in NB4 and U937 cells similar to all-trans RA (ATRA). A specific RARalpha antagonist, Ro41-5253, efficiently suppressed the upregulation of TM by ATRA and Am80 in NB4 cells, U937 cells and HUVECs. In contrast, only when both RARalpha and RARbeta antagonists were preincubated, downregulation of TF by the retinoids was suppressed in NB4 cells. Furthermore, 1,25(OH)2D3 has been shown to have anticoagulant effects on several monocytic leukemia cells and monocytes similar to RAs. These results indicate the mechanically distinct transactivation and transrepression functions of RARs, the major role of RARalpha in TM upregulation by retinoids in leukemic cells and HUVECs, and the cooperative role of RARalpha and RARbeta in TF downregulation by retinoids. It is also implied that synthetic retinoids and vitamin D derivatives will provide very useful means to control distinct targets--TM and TF genes--at the level of transcription. Synthetic retinoids and vitamin D derivatives may develop as new types of antithrombotic and antiatherosclerotic agents which change the character of cells as well as malignant cell differentiation inducers.