on September 12, 2002
Published online before print September 12, 2002, doi: 10.1161/01.ATV.0000037102.31086.F4
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Submitted on August 6, 2002
Accepted on August 15, 2002
Pharmacological Potentiation of Natriuretic Peptide Limits Polymorphonuclear Neutrophil-Vascular Cell Interactions
El Mostafa Mtairag ;
From U460 INSERM CHU X (E.M.M., S.R., M.-P.J., O.M., J.-B.M.), Cardiovascular Remodeling, Paris, France; Hassan II University (E.M.M., S.R., M.O.), Schools of Sciences Ain chok and Ben M'Sik, Department of Biology, Casablanca, Morocco; U36 INSERM Collège de France (X.H.), Paris, France; and U479 INSERM CHU X (C.P.), Paris, France.
* To whom correspondence should be addressed. E-mail: u460{at}bichat.inserm.fr.
Objective—Activated polymorphonuclear neutrophils (PMNs) are the main source of circulating neutral endopeptidase (NEP). We tested the hypothesis that NEP inhibition could potentiate the effect of atrial natriuretic peptide (ANP) on PMN-vascular cell interactions in vitro.
Methods and Results—ANP alone and its potentiation by retrothiorphan, the NEP inhibitor, significantly inhibited superoxide, lysozyme, and matrix metalloproteinase (MMP)-9 release by N-formyl-Met-Leu-Phe-stimulated PMNs. Activated PMNs degraded exogenous ANP, which was prevented by NEP inhibition. Hypoxia significantly increased the adhesion of PMNs to endothelial cells and their subsequent MMP-9 release by 60% and 150%, respectively (P<0.01). ANP and its potentiation by retrothiorphan limited PMN adhesion to hypoxic endothelial cells and thus decreased their MMP-9 release (P<0.01). Smooth muscle cells (SMCs) incubated with conditioned medium of N-formyl-Met-Leu-Phe-stimulated PMNs exhibited morphological and biochemical changes characteristic of apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling positivity, nuclear condensation/fragmentation, poly ADP-ribose polymerase cleavage, and DNA laddering). SMC detachment and subsequent apoptosis could be related to leukocyte elastase-induced pericellular proteolysis, inasmuch as both events are inhibited by elastase inhibitors. ANP and its potentiation by retrothiorphan were able to limit elastase release, fibronectin degradation, and SMC apoptosis.
Conclusions—ANP potentiation by NEP inhibition could limit PMN activation and its consequences on vascular cells.
Key words: neutral endopeptidase inhibitors • endothelial cells • smooth muscle cells • proteases • hypoxia • anoikis
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