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.

Mean Platelet Volume and Vitamin D Level

“…Therefore, vitamin D derivatives may be developed as new types of antithrombotic agents. A study conducted by Kebapcilar et al [38] on women diagnosed with primary ovarian insufficiency showed a negative correlation between MPV and the vitamin D level, and Koyama et al [37] found similar results. The results of our study also coincide with these studies.…”

“…Consequently, a high MPV increases cardiac disease risk. One previously reported mechanism suggests that vitamin D exerts anticoagulant effects by upregulating the expression of an anticoagulant glycoprotein (thrombomodulin) and downregulating the expression of a critical coagulation factor (tissue factor) in monocytes [37]. Therefore, vitamin D derivatives may be developed as new types of antithrombotic agents.…”

Effect of Vitamin D deficiency in lower extremity and pulmonary venous thromboembolism

“…It is described as a common global problem with a prevalence of 30-50% population 3,4 , and is involved in CVDs and venous thromboembolism (VTE) 5,6,[9][10][11] . In leukemic patients, active vitamin D stimulates anticoagulant effects through tissue factor downregulation and thrombomodulin upregulation [12][13][14] . Vitamin D receptors are involved in thrombosis 15,16 .…”

Relationship between mean platelet volume and vitamin D deficiency in gestational diabetes mellitus

“…Furthermore, new evidence has suggested that vitamin D may play an important role in preventing platelet activation as well as decreasing fibrinolysis and thrombosis. Thus vitamin D deficiency may lead to an increased MPV (16). In a new study it has been demonstrated that there is a strong association between a low vitamin D level and a high MPV in healthy volunteers (17).…”