Aliskiren, a renin inhibitor, downregulates TNF-α-induced tissue factor expression in HUVECS

Abstract

Angiotensin (Ang)II, the effector arm of the locally active renin—angiotensin system (RAS), modulates Tissue Factor (TF), the principal initiator of blood coagulation and a key promoter of atherothrombotic events. Consistent with that knowledge, previous data showed inhibitory properties of angiotensin-converting enzyme inhibitor (ACEI)s and angiotensin II type-1 receptor blocker (ARB)s, but no data are available about the effect of renin inhibition. We aimed to evaluate whether aliskiren, a direct renin inhibitor (DRI), modulates TNF-α-stimulated TF expression in cultured human umbilical vein endothelial cells (HUVECs). Zofenopril, an ACEI, and olmesartan, an ARB, were the controls. HUVECs were incubated with experimental drugs (1 nM) 30 min prior to TNF-α stimulation (0.1 ng/ml × 4 h). Main evaluation variables were procoagulant activity (single-stage clotting assay), TF antigen (ELISA) and mRNA expression (real-time polymerase chain reaction) in cell lysates. TNF-α stimulated procoagulant activity and increased TF antigen and mRNA expression. Aliskiren inhibited TNF-α-mediated TF stimulation; zofenopril and olmesartan exerted a comparable effect. We conclude that aliskiren, a DRI, downregulates TNF-α-stimulated TF expression in HUVECs, possibly as a reflection of endothelial renin activation by the cytokine.