Compound 21, a selective angiotensin II type 2 receptor agonist, downregulates lipopolysaccharide-stimulated tissue...

Intricate interrelationships connect tissue factor (TF), the principal initiator of the clotting cascade, to inflammation, a cross-talk amplified by locally active angiotensin II, a proinflammatory agent with direct TF-stimulating properties mediated by the angiotensin II type 1 receptor (AT1R)s. However, angiotensin II also stimulates angiotensin II type 2 receptor (AT2R)s and they may as well contribute to TF expression, a possibility in need of further evaluation. We investigated the effect of C21, a highly specific AT2R agonist, on TF antigen (ELISA), procoagulant activity (PCA, one-stage clotting assay) and TF-mRNA (real-time PCR) in peripheral blood mononuclear cell (PBMC)s activated by lipopolysaccharide (LPS), a pro-inflammatory and procoagulant stimulus. C21 downregulated LPS-stimulated TF antigen, PCA and TF mRNA, an effect abolished by PD123 319, a selective AT2R antagonist, and left unchanged by omesartan, a selective AT1R antagonist. PD123 319 per se did not affect LPS-induced TF expression while omesartan inhibited and BAY 11-7082, a specific NFκB inhibitor, abolished endotoxin-activated procoagulant activity (PCA). C21, a selective AT2R agonist, downregulates the transcriptional expression of TF in LPS-activated PBMCs, a finding consistent with the existence in PBMCs of AT2Rs whose stimulation attenuates inflammation-mediated procoagulant responses. The data open insofar unexplored and potentially relevant facets to our understanding of the complex links connecting angiotensin II to inflammation and coagulation.