Document Detail

Smad2-Dependent Protease Nexin-1 Overexpression Differentiates Chronic Aneurysms From Acute Dissections of Human Ascending Aorta.
MedLine Citation:
PMID:  23814118     Owner:  NLM     Status:  Publisher    
OBJECTIVE: Tissue activation of proteolysis is involved in acute intramural rupture (dissections, acute ascending aortic dissection) and in progressive dilation (aneurysms, thoracic aneurysm of the ascending aorta) of human ascending aorta. The translational aim of this study was to characterize the regulation of antiproteolytic serpin expression in normal, aneurysmal, and dissecting aorta.
APPROACH AND RESULTS: We explored expression of protease nexin-1 (PN-1) and plasminogen activator inhibitor-1 and their regulation by the Smad2 signaling pathway in human tissue and cultured vascular smooth muscle cells (VSMCs) of aneurysms (thoracic aneurysm of the ascending aorta; n=46) and acute dissections (acute ascending aortic dissection; n=10) of the ascending aorta compared with healthy aortas (n=10). Both PN-1 and plasminogen activator inhibitor-1 mRNA and proteins were overexpressed in medial tissue extracts and primary VSMC cultures from thoracic aneurysm of the ascending aorta compared with acute ascending aortic dissection and controls. Transforming growth factor-β induced increased PN-1 expression in control but not in aneurysmal VSMCs. PN-1 and plasminogen activator inhibitor-1 overexpression by aneurysmal VSMCs was associated with increased Smad2 binding on their promoters and, functionally, resulted in VSMC self-protection from plasmin-induced detachment and death. This phenomenon was restricted to aneurysms and not observed in acute dissections.
CONCLUSIONS: These results demonstrate that epigenetically regulated PN-1 overexpression promotes development of an antiproteolytic VSMC phenotype and might favor progressive aneurysmal dilation, whereas absence of this counter-regulation in dissections would lead to acute wall rupture.
Delphine Gomez; Ketty Kessler; Luciano F Borges; Benjamin Richard; Ziad Touat; Véronique Ollivier; Silvana Mansilla; Marie-Christine Bouton; Soleyman Alkoder; Patrick Nataf; Martine Jandrot-Perrus; Guillaume Jondeau; Roger Vranckx; Jean-Baptiste Michel
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-6-27
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  -     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-7-1     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
From the Inserm, UMR 698, Paris 7-Denis Diderot University, CHU X. Bichat, Paris, France (D.G., K.K., L.F.B., B.R., Z.T., V.O., S.M., M.-C.B., M.J.-P., G.J., R.V., J.-B.M.); Department of Morphology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, Brazil (L.F.B.); Department of Cardiovascular Surgery, Xavier Bichat Hospital, Paris, France (S.A., P.N.); and Centre National de Référence pour le syndrome de Marfan et apparentés, Hôpital Bichat, Paris, France (G.J.).
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