Effects Of ACEI And ARB On Expression Of Tissue Factor In Human Monocytes

Angiotensin converting enzyme (ACE) inhibitors, originally designed to treat hypertension, were quickly demonstrated to confer hemodynamic and survival benefit to patients with congestive heart failure. Extending this paradigm to patients with left ventricular dysfunction (LVD) post-myocardial infarction (MI), ACE inhibitors were shown to attenuate ventricular remodeling and reduce mortality. An unexpected finding that ACE inhibitors could reduce the incidence of myocardial infarction and the risk of recurrent myocardial infarction prompted enormous interest in their anti-ischemic potential .Tissue factor (TF) the initiator of blood coaguation , plays a pivotal role in arterial thrombosis that occurs after atherosclerotic plaque fissuring. Because monocytes synthesize TF and cotain several components of the renin-angiotensin system, we investigated the possibility that ACE inhibitors and angiotensin II ATj antagonists (ARB) could modulate monocyte TF expression .Part I:Effects of ACEI and ARB on the procoagualant activity of monocytesMononuclear leukocytes from healthy human umbilical veins were incubated with bacterial lipopolysaccharide (LPS) in presence or absence of different ACE inhibitors for 4 hours at 37 'C .At the end of incubation,the cells(3xl06/mL) were disrupted by 3 freeze-thaw cycles. TF Procoagulant activity was assessed by a one-stage clotting assay. Fosinopril reduced TF expression in LPS-stimulated mononuclear leukocytes ,as measured by ? 60%. The effect was dose -dependent and was attributable to ACE inhibition,given that other ACE inhibitors,such as captopril ,and a valsartan ,an antagonist of the angiotensin II ATt receptor(ARB), caused a comparable reduction in TF activity.Part II. ACEI and ARB Downregulate the expression of TFmRNA in monocytesTo determine the steady-state levels of TF mRNA,We prepared from untreated control cells or from human monocyes treated with LPS with or without Valsartan or Fosinopril,captopril was reverse transcribed and used for parallel assay of TF and GAPDH mRNA by PCR amplification. The results showed that LPS-mediated increased levels of TFmRNA were inhibited by ACEI and ARBPart III Inhibitory effects of ACEI and ARB on the Transcription NF-K B in monocytesIn this report, we used western blotting to investigate the effect of ACEI and ARB on NF- K B activation induced by various agents. NF- K B,a ubiquitous nuclear transcription factor, which consists of c-Rel and P65subunits ,regulates the expression of various genes.Transcriptlonal activation of human TF gene inmonocytes exposed to LPS is mediated by phosphorylation and degradation of inhibitor protein I K B a ,the translocation of p65 subunits to the nucleus binding to a K B site in the TF promoter. The date showed that LPS-dependent phosphorylation and degradation of I K B a was markedly impaired in ACEI and ARE -treated monocytes and the translocation of p65 subunit to the nucleus was inhibited at the same .The finding that ACEI and ARB can potentially modulate TF expression by monocytes 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 .