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oai:repisalud.isciii.es:20.500.12105/271622026-01-22T01:20:37Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587

00925njm 22002777a 4500 dc Mehrkens, Dennis author Dohr, Johannes author Nettersheim, Felix Sebastian author Ballmann, Felix author Bastigkeit, Jil author Brückner, Alexander author Geissen, Simon author De Vore, Lauren author Fitsch, Cedric author Diekmann, Chris author de la Fuente-Alonso, Andrea author Schelemei, Patrik author Picard, Felix Ruben author Kochen, Malte author Arkenberg, Per author Rappenecker, Anna author Ahdab, Maysam author Nemade, Harshal author Narayan, Suchitra author Braumann, Simon author Kreuzberg, Wiebke author Hof, Alexander author Guthoff, Henning author Mensah, Benedicta Quaye author Lechner, Sebastian author Guala, Andrea author Evangelista, Artur author Teixido-Tura, Gisela author Nistal, J Francisco author Campanero, Miguel R author Kaemmerer, Harald author Wolf, Zsuzsanna author Holdenrieder, Stefan author Groenink, Maarten author van Andel, Mitzi author Mieremet, Arnout author Pfeiler, Susanne author Gerdes, Norbert author Flögel, Ulrich author Zimmermann, Laura-Maria author Sengle, Gerhard author Eich, Marie-Lisa author Schömig-Markiefka, Birgid author Adam, Matti author Fleischmann, Bernd K author Wenzel, Daniela author Redondo, Juan Miguel author de Waard, Vivian author Klinke, Anna author Baldus, Stephan author Mollenhauer, Martin author Winkels, Holger author 2025-12-17 Patients suffering from Marfan syndrome (MFS), the most prevalent inherited connective tissue disorder, face premature mortality due to dissection and rupture of thoracic aortic aneurysms. Here, we questioned whether myeloperoxidase (MPO), a leucocyte-derived enzyme with high affinity to the vessel wall, contributes to aortic remodelling in MFS. Plasma MPO levels were evaluated in MFS patients and healthy controls. Thoracic aortic aneurysm formation was determined in heterozygous transgenic Fbn1C1041G/+ (MFS) mice, MPO-deficient MFS mice (MFSxMpo-/-), and MFS mice treated with an MPO inhibitor by ultrasound and histology.MFS patients exhibited increased circulating MPO levels and marked aortic MPO deposition. In MFS mice, MPO-deficiency reduced aortic elastin fragmentation and aneurysm formation. RNA sequencing revealed an inflammatory gene program in aortic endothelial cells isolated from MFS mice in comparison to WT and MFSxMpo-/- mice. This was accompanied by enhanced endothelial expression of the leucocyte adhesion molecule ICAM-1, increased leucocyte adhesion, and, consequently, leucocyte infiltration in MFS aortae. Moreover, MPO directly contributed to adverse extracellular matrix remodelling through overproduction of reactive oxygen species and subsequent vascular protein modifications leading to enhanced matrix metalloproteinase 2/9 activity. Lastly, treatment of MFS mice with the orally available MPO inhibitor AZM198 attenuated TAA formation. MPO is increased in MFS and contributes to thoracic aortic dilatation by inducing inflammatory endothelial activation, oxidative stress, and adverse extracellular matrix remodelling. Pharmacological and genetic inhibition of MPO reduced MFS-related aortic dilation in mice, highlighting MPO as a promising therapeutic target in MFS. Cardiovasc Res. 2025 Dec 17:cvaf248 Cardiovascular Research 41403006 https://hdl.handle.net/20.500.12105/27162 Marfan syndrome Aortic aneurysm Inflammation Myeloperoxidase Endothelial cells Myeloperoxidase aggravates thoracic aortic aneurysm formation in Marfan disease.