© 2000 American Heart Association, Inc.
Clinical Research |
Angiotensin-Converting Enzyme Inhibitors Downregulate Tissue Factor Synthesis in Monocytes
From the "Antonio Taticchi" Unit for Atherosclerosis and Thrombosis (E.N., A.D.S., R.L.), Department of Vascular Medicine and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, and the Laboratory of Pharmacology of Atherosclerosis and Thrombosis (M.C., E.T.), Institute of Pharmacological Sciences, University of Milan, Italy.
Correspondence to Dr Roberto Lorenzet, Consorzio Mario Negri Sud, Via Nazionalé 66030 S Maria Imbaro, Italy. E-mail lorenzet{at}cmns.mnegri.it
Abstract—Angiotensin-converting
enzyme (ACE) inhibitors reduce the risk of recurrent
myocardial infarction in patients with left ventricular
dysfunction. Tissue factor (TF), the initiator of blood coagulation,
plays a pivotal role in arterial thrombosis that occurs
after atherosclerotic plaque fissuring. Because monocytes synthesize TF
and contain several components of the renin-angiotensin
system, we investigated the possibility that ACE inhibitors
could modulate monocyte TF expression. Mononuclear leukocytes from
healthy volunteers were incubated with endotoxin in the presence or
absence of different ACE inhibitors. Captopril reduced TF
expression in endotoxin-stimulated mononuclear leukocytes, as measured
by a 1-stage clotting assay and ELISA analysis, by 
60%. The
effect was dose-dependent and was attributable to ACE inhibition, given
that other ACE inhibitors, such as idrapril or fosinopril,
and losartan, an antagonist of the
angiotensin II AT1 receptor, caused a
comparable reduction in TF activity. Reverse transcriptase–polymerase
chain reaction indicated that endotoxin-mediated increased levels of TF
mRNA were inhibited by ACE inhibitors. Moreover,
endotoxin-induced nuclear factor-
B translocation to the promoter
region of the gene encoding for TF was markedly inhibited by captopril.
The finding that ACE inhibitors and angiotensin
II AT1 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 effect of these drugs might be
explained, at least in part, by their ability to reduce TF expression
in monocytes.
Key Words: angiotensin • coagulation • leukocyte
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