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 RARγ; Ch55, which does not bind to cytoplasmic retinoic acid-binding protein
(CRABP); and a specific RARα 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 RARα 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 RARα and RARβ antagonists were preincubated, downregulation of TF by the retinoids
was suppressed in NB4 cells. Furthermore, l,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 RARα in TM upregulation by retinoids in leukemic
cells and HUVECs, and the cooperative role of RARα and RARβ 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.
Keywords:
Synthetic retinoids - retinoic acid receptor (RAR) - tissue factor (TF) - thrombomodulin
(TM) - aging
