Author:
Mehrkens Dennis,Nettersheim Felix Sebastian,Ballmann Felix,Bastigkeit Jil,Brückner Alexander,Dohr Johannes,Geissen Simon,De Vore Lauren,Schelemei Patrik,Picard Felix Ruben,Kochen Malte,Braumann Simon,Kreuzberg Wiebke,Hof Alexander,Guthoff Henning,Brandtner Adrian,Mensah Benedicta Quaye,Groenink Maarten,van Andel Mitzi,Mieremet Arnout,Pfeiler Susanne,Gerdes Norbert,Flögel Ulrich,Zimmermann Laura-Maria,Sengle Gerhard,Eich Marie-Lisa,Schömig-Mariefka Birgid,Adam Matti,Fleischmann Bernd K,Wenzel Daniela,de Waard Vivian,Klinke Anna,Baldus Stephan,Mollenhauer Martin,Winkels Holger
Abstract
AbstractMarfan syndrome (MFS) is the most prevalent inherited connective tissue disorder, still remains uncurable, and is characterized by high mortality at early age driven by dissection and rupture of thoracic aortic aneurysms. MFS is caused by mutations in the fibrillin-1 gene and aberrant TGFß signaling.Here we addressed whether myeloperoxidase (MPO), a leukocyte derived enzyme with potent matrix modulating properties also influences the aortic phenotype in MFS.MFS patients displayed increased circulating MPO levels compared to controls as well as marked aortic MPO deposition. In an MFS mouse model, MPO induced inflammatory endothelial activation and endothelial to mesenchymal transition which triggered aortic leukocyte recruitment. Moreover, MPO directly contributed to adverse extracellular matrix remodeling by promoting oxidative stress and nitration of proteins within the vascular wall. Genetic MPO deficiency and pharmacological MPO inhibition attenuated MFS-related aneurysm formation. We herein identify MPO as a critical mediator of MFS-related thoracic aortic aneurysm formation and - in the absence of any pharmacological treatment so far in this disease - a first anti-inflammatory target to modulate disease progression.
Publisher
Cold Spring Harbor Laboratory