Angiotensin-converting enzyme inhibitors downregulate tissue factor synthesis in monocytes

Angiotensin-converting enzyme (ACE) inhibitors reduce the risk of recurrent myocardial infarction in patients with left ventricular dysfunction. Tissu e factor (TF), the initiator of brood coagulation, plays a pivotal role in arterial thrombosis that occurs after atherosclerotic plaque fissuring. Bec ause monocytes synthesize TF and contain several components of the renin-an giotensin system, we investigated the possibility that ACE inhibitors could modulate monocyte TF expression. Mononuclear leukocytes from healthy volun teers were incubated with endotoxin in the presence or absence of different ACE inhibitors. Captopril reduced TF expression in endotoxin-stimulated mo nonuclear leukocytes, as measured by a I-stage clotting assay and ELISA ana lysis, by approximate to 60%. The effect was dose-dependent and was attribu table to ACE inhibition, given that other ACE inhibitors, such as idrapril or fosinopril, and losartan, an antagonist of the angiotensin II AT, recept or, caused a comparable reduction in TF activity. Reverse transcriptase-pol ymerase chain reaction indicated that endotoxin-mediated increased levels o f TF mRNA were inhibited by ACE inhibitors. Moreover, endotoxin-induced nuc lear factor-KB translocation to the promoter region of the gene encoding fo r TF was markedly inhibited by captopril. The finding that ACE inhibitors a nd angiotensin II AT(1) antagonists can potentially modulate TF expression by mononuclear cells has important biological and therapeutic implications for the evolution of thrombi. Our results suggest that the anti-ischemic ef fect of these drugs might be explained, at least in part, by their ability to reduce TF expression in monocytes.