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 approximately 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 AT(1) 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-kappaB translocation to the promoter region of the gene encoding for TF was markedly inhibited by captopril. The finding that ACE inhibitors and 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 effect of these drugs might be explained, at least in part, by their ability to reduce TF expression in monocytes.

Angiotensin-converting enzyme inhibitors downregulate tissue factor synthesis in monocytes / E. Napoleone, A. Di Santo, M. Camera, E. Tremoli, R. Lorenzet. - In: CIRCULATION RESEARCH. - ISSN 0009-7330. - 86:2(2000 Feb 04), pp. 139-143. [10.1161/01.RES.86.2.139]

Angiotensin-converting enzyme inhibitors downregulate tissue factor synthesis in monocytes

M. Camera;E. Tremoli
Penultimo
;
2000

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 approximately 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 AT(1) 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-kappaB translocation to the promoter region of the gene encoding for TF was markedly inhibited by captopril. The finding that ACE inhibitors and 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 effect of these drugs might be explained, at least in part, by their ability to reduce TF expression in monocytes.
Endotoxins; NF-kappa B; Captopril; Losartan; Dimerization; Humans; Receptor, Angiotensin, Type 1; Gene Expression; Receptor, Angiotensin, Type 2; Angiotensin Receptor Antagonists; Cell Nucleus; Antihypertensive Agents; Proto-Oncogene Proteins c-rel; RNA, Messenger; Blood Coagulation; Thromboplastin; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Monocytes
Settore BIO/14 - Farmacologia
Article (author)
File in questo prodotto:
File Dimensione Formato  
139.full.pdf

accesso solo dalla rete interna

Tipologia: Publisher's version/PDF
Dimensione 306.39 kB
Formato Adobe PDF
306.39 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/187857
Citazioni
  • ???jsp.display-item.citation.pmc??? 15
  • Scopus 122
  • ???jsp.display-item.citation.isi??? 114
social impact