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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1578.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Soluble Guanylate Cyclase Agonists Inhibit Expression and Procoagulant Activity of Tissue Factor

Mikhail A. Sovershaev; Elena M. Egorina; John-Bjarne Hansen; Bjarne Østerud; Pál Pacher; Johannes-Peter Stasch; Oleg V. Evgenov

From the Department of Medicine (M.A.S., J.-B.H.), University Hospital of Northern Norway, Tromsø; the Department of Biochemistry, Institute of Medical Biology (M.A.S., E.M.E., B.Ø.) and the Center for Atherothrombotic Research, Institute of Clinical Medicine (J.-B.H.), University of Troms, Norway; the Department of Anesthesia, Critical Care, and Pain Medicine (M.A.S., E.M.E., O.V.E.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass; the Laboratory of Physiological Studies (P.P.), National Institutes of Health/NIAAA, Bethesda, Md; and the Institute of Cardiovascular Research (J.-P.S.), Bayer Schering Pharma AG, Wuppertal, Germany.

Correspondence to Oleg V. Evgenov, MD, PhD, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Gray/Bigelow 444, Boston, MA 02114. E-mail oevgenov{at}partners.org; oleg.evgenov@gmail.com.

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.

Methods and 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-. The sGC agonists also suppressed transcriptional activity of NF-B. A siRNA-mediated knockdown of the 1-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.

Agonists of soluble guanylate cyclase, BAY 41-2272 and BAY 58-2667, inhibit expression and procoagulant activity of tissue factor in human monocytes, stimulated with lipopolysaccharide, and vascular endothelial cells, stimulated with tumor necrosis factor-. These novel pharmacophores might provide therapeutic benefits in cardiovascular diseases associated with enhanced procoagulant and inflammatory response.

Key Words: tissue factor • procoagulant activity • soluble guanylate cyclase • BAY 41-2272 • BAY 58-2667