Soluble guanylate cyclase agonists inhibit expression and procoagulant activity of tissue factor.
OBJECTIVE
Tissue factor (TF), a major initiator of blood coagulation, contributes to inflammation, atherosclerosis, angiogenesis, and vascular remodeling. Pharmacological agonists of soluble guanylate cyclase (sGC) attenuate systemic and pulmonary hypertension, vascular remodeling, and platelet aggregation. However, the influence of these novel pharmacophores on TF is unknown.


RESULTS
We evaluated effects of BAY 41-2272 and BAY 58-2667 on expression and activity of TF in human monocytes and umbilical vein endothelial cells (HUVECs). Both compounds reduced expression of active TF protein in monocytes stimulated with lipopolysaccharide, as demonstrated by immunoblotting and a TF procoagulant activity assay. In-cell Western assay revealed that this effect was associated with a marked reduction of total and surface TF presentation. Furthermore, BAY 41-2272 and BAY 58-2667 decreased TF protein expression and the TF-dependent procoagulant activity in HUVECs stimulated with TNF-alpha. The sGC agonists also suppressed transcriptional activity of NF-kappaB. A siRNA-mediated knockdown of the alpha1-subunit of sGC in monocytes and HUVECs confirmed that the inhibitory effect of BAY 41-2272 and BAY 58-2667 on TF expression is mediated through the sGC-dependent mechanisms.


CONCLUSIONS
Inhibition of TF expression and activity by sGC agonists might provide therapeutic benefits in cardiovascular diseases associated with enhanced procoagulant and inflammatory response.
Sovershaev
Mikhail A
MA
Department of Medicine, University Hospital of Northern Norway, Tromsø, Norway.
Egorina
Elena M
EM
Hansen
John-Bjarne
JB
Østerud
Bjarne
B
Pacher
Pál
P
Stasch
Johannes-Peter
JP
Evgenov
Oleg V
OV
D000328:Adult; D001565:Benzoates / Q000494:pharmacology*; D002470:Cell Survival; D006152:Cyclic GMP / Q000032:analysis; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006162:Guanylate Cyclase / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D013925:Thromboplastin / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000276:immunology
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D001565:Benzoates; D016328:NF-kappa B; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; C480588:BAY 58-2667; D013925:Thromboplastin; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP