Koyama T, Hirosawa S
First Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Semin Thromb Hemost. 1998;24(3):217-26. doi: 10.1055/s-2007-995845.
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.
我们最近发现，维甲酸（RA）通过上调血栓调节蛋白（TM）和下调急性早幼粒细胞白血病（APL）及单核细胞白血病细胞中组织因子（TF）的表达发挥抗凝作用。已经鉴定出两类核RA受体，即维甲酸受体（RAR）和类视黄醇X受体。每类受体都由三个亚型组成。我们使用了几种合成类视黄醇来确定哪些受体亚型参与调控APL细胞NB4、单核细胞白血病细胞U937和人脐静脉内皮细胞（HUVEC）中TM和TF的表达。已证明对RARγ没有结合亲和力的Am80、不与细胞质维甲酸结合蛋白（CRABP）结合的Ch55以及一种特异性RARα激动剂Ro40 - 6055，在NB4和U937细胞中与全反式维甲酸（ATRA）类似，能上调TM并下调TF。一种特异性RARα拮抗剂Ro41 - 5253有效抑制了NB4细胞、U937细胞和HUVEC中ATRA和Am80对TM的上调作用。相反，仅在预先孵育RARα和RARβ拮抗剂时，NB4细胞中类视黄醇对TF的下调作用才受到抑制。此外，已证明1,25(OH)2D3对几种单核细胞白血病细胞和单核细胞具有与RA类似的抗凝作用。这些结果表明RAR具有机械上不同的反式激活和反式抑制功能，RARα在白血病细胞和HUVEC中类视黄醇上调TM过程中起主要作用，以及RARα和RARβ在类视黄醇下调TF过程中起协同作用。还暗示合成类视黄醇和维生素D衍生物将提供非常有用的手段，在转录水平控制不同的靶点——TM和TF基因。合成类视黄醇和维生素D衍生物可能发展成为新型抗血栓形成和抗动脉粥样硬化药物，既能改变细胞特性，又能作为恶性细胞分化诱导剂。
