Myeloperoxidase aggravates thoracic aortic aneurysm formation in Marfan disease.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
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Mehrkens Dennis, Dohr Johannes, Nettersheim Felix Sebastian, Ballmann Felix, Bastigkeit Jil, Brückner Alexander, Geissen Simon, De Vore Lauren, Fitsch Cedric, Diekmann Chris, de la Fuente-Alonso Andrea, Schelemei Patrik, Picard Felix Ruben, Kochen Malte, Arkenberg Per, Rappenecker Anna, Ahdab Maysam, Nemade Harshal, Narayan Suchitra, Braumann Simon, Kreuzberg Wiebke, Hof Alexander, Guthoff Henning, Mensah Benedicta Quaye, Lechner Sebastian, Guala Andrea, Evangelista Artur, Teixido-Tura Gisela, Nistal J Francisco, Campanero Miguel R, Kaemmerer Harald, Wolf Zsuzsanna, Holdenrieder Stefan, Groenink Maarten, van Andel Mitzi, Mieremet Arnout, Pfeiler Susanne, Gerdes Norbert, Flögel Ulrich, Zimmermann Laura-Maria, Sengle Gerhard, Eich Marie-Lisa, Schömig-Markiefka Birgid, Adam Matti, Fleischmann Bernd K, Wenzel Daniela, Redondo Juan Miguel, de Waard Vivian, Klinke Anna, Baldus Stephan, Mollenhauer Martin, Winkels Holger
Аннотация
METHODS AND RESULTS: 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.
CONCLUSION: 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.