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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, RESULTS. Meshes: Acute Disease, Adult, Aged, Aged, 80 and over, Aneurysm, Dissecting, Aortic Aneurysm, Thoracic, Aortic Valve, Binding Sites, Biomarkers, Cells, Cultured, Chronic Disease, Female, Fibrillins, Genetic Predisposition to Disease, Genotype, Heart Valve Diseases, Humans, Male, Marfan Syndrome, Microfilament Proteins, Middle Aged, Muscle, Smooth, Vascular, Mutation, Myocytes, Smooth Muscle, Phenotype, Plasminogen Activator Inhibitor 1, Promoter Regions, Genetic, RNA, Messenger, Risk Factors, Serpin E2, Smad2 Protein, Time Factors, Transforming Growth Factor beta1, Up-Regulation.
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Does smad2-dependent protease nexin-1 overexpression differentiate chronic aneurysms from acute dissections of human ascending aorta? Context: 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. 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.
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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. Final Decision: yes