Role of cyclic AMP in promoting the thromboresistance of human endothelial cells by enhancing thrombomodulin and decreasing tissue factor activities

Abstract

The effects of forskolin, prostaglandin E1 (PGE1), dibutyryl cyclic AMP (db cyclic AMP), dibutyryl cyclic GMP (db cyclic GMP) and 3‐isobutyl‐1‐methyl‐xanthine (IBMX) were investigated on the expression of tissue factor and thrombomodulin activities on the surface of human saphenous vein endothelial cells (HSVEC) in culture. Forskolin (10−6 to 10−4 m), PGE1 (10−7 to 10−5 m) and db cyclic AMP (10−4 to 10−3 m) caused a concentration‐dependent decrease of cytokine‐induced tissue factor activity. Similar concentrations of forskolin, PGE1 and db cyclic AMP enhanced significantly constitutive thrombomodulin activity and reversed the decrease of this activity caused by interleukin‐1 (IL‐1). IBMX (10−4 m) decreased tissue factor activity and enhanced the effect of forskolin on tissue factor and thrombomodulin activities. Forskolin (10−4 m) decreased the IL‐1‐induced tissue factor mRNA and increased the thrombomodulin mRNA level. IL‐1 did not change the thrombomodulin mRNA level after 2 h of incubation with HSVEC in culture. Dibutyryl cyclic GMP (10−4 m to 10−3 m) did not influence tissue factor or thrombomodulin activity. Our data suggest that elevation of intracellular cyclic AMP levels may participate in the regulation of tissue factor and thrombomodulin expression, thus contributing to promote or restore antithrombotic properties of the endothelium.

Angiogenesis inhibitor SR 25989 upregulates thrombospondin‐1 expression in human vascular endothelial cells and foreskin fibroblasts

“…This has led to the development of a variety of pharmacological agents inhibiting different stages of angiogenesis, some of which are already undergoing clinical trials as adjuvants to potentiate conventional cancer therapy (Folkman, 199513). In the present paper, we show that the thienopyridine SR 25989, a potent inhibitor of endothelial cell proliferation and migration in vitro (Klein-Soyer et al, 1994) displaying anti-angiogenic properties in vitro and in viva, (Cazenave and Herbert, 1992;Klein-Soyer et al, 1993) regulates the expression of several proteins contributing to tissue remodeling in growing cells. Intracellular proteins involved in activa- tion and inhibition of fibrinolysis were moderately increased (30 to 76% over control values) in EC, but the effect on the activators of fibrinolysis tPA and uPA was of the same magnitude and concomitant to that of the inhibitor PA&l. Thus it seems unlikely that the action of SR 25989 could be related to modulation of the fibrinolytic system in cells.…”

Regulation of Thrombomodulin Expression in Human Vascular Smooth Muscle Cells by COX-2–Derived Prostaglandins

“…30 Accordingly, in cell culture experiments, TM was found to be upregulated by cAMP in SMCs. 31,32 cAMP also upregulated TM expression in cultured endothelial cells 33 and in embryonal carcinoma cells. 34 Importantly, prostacyclin infusion was able to increase soluble TM levels in patients with pulmonary arterial hypertension.…”

Mutations in Promoter Region of Thrombomodulin and Venous Thromboembolic Disease

“…TM biosynthesis is decreased by tumor necrosis factor (TNF), 6 -15 interleukin-1, 11,16 endotoxin, 17 hypoxia, 18 and transforming growth factor ␤ (TGF␤). 19 Agonists, including retinoic acid, 20 -22 cAMP, 10,11,[23][24][25][26][27][28][29] histamine, 30 forskolin, 23,25 phorbol esters, 11,23,31,32 vascular endothelial growth factor (VEGF), 33 and thrombin, 34 enhance TM transcription in different cell types. Heat shock of vascular endothelial cells induces an upregulatory transcriptional response that abrogates the suppressive effect of TNF.…”