Background: Marfan syndrome (MFS) is the most prevalent inherited connective tissue disorder (fibrillin‐1 gene mutation) characterized by aortic root aneurysm formation with subsequent aortic dissection contributing to a shortened lifespan. Fibrillin-1 is a major component of extracellular microfibrils, providing a scaffold for elastic-fiber formation and maturation. Mutant fibrillin-1 disrupts microfibril formation, which leads to aortic destabilization and increases its vulnerability to hemodynamic injury. Pharmacological therapy is limited to ß-blockage that fail to halt abnormal aortic growth, prevents aortic dissection or death. Therefore, novel pharmacological strategies are needed to effectively treat MFS patients. MFS is accompanied by endothelial dysfunction for which the molecular mechanisms are unknown. In addition, inflammatory processes are key drivers of disease progression in MFS. Neutrophils are the most abundant circulatory immune cells, which secrete the heme enzyme myeloperoxidase (MPO). Both, neutrophils and MPO, have been involved in the progression of cardiovascular diseases. We thus hypothesize that MPO may adversely affect vascular signal transduction and thereby aggravate aortic aneurysm formation in MFS.

Methods and Results: Tissue ELISAs of aortic homogenates showed increased MPO expression in heterozygous fibrillin-1^C1041G/+ (Fbn1) transgenic mice, a mouse model of Marfan’s disease, compared to wildtype controls. To investigate the role of MPO in MFS, MPO-deficient (Mpo^-/-) mice were bred with Fbn1 mice to obtain Fbn1^C1041G/+/Mpo^-/- mice (Fbn1-DKO). Ultrasound analysis of aortic root and ascending aorta in Fbn1 animals showed an increased aortic diameter and vascular stiffness compared to controls and Fbn1-DKO mice. Histological analysis of aortic root sections showed increased elastic fiber fragmentation - indicative of disease progression - in Fbn1 mice whereas Fbn1-DKO and controls showed less and comparable fragmentation. Furthermore, zymography revealed an increased activity of MMP 2 & 9 in Fbn1 mice, which stayed at control levels in Fbn1-DKO mice. MPO activity can modify NO-mediated vasodilatation. Fbn1 mice had increased 3-nitryotyrosine immunostaining in aortic root sections compared to wildtype and Fbn1-DKO mice, indicating MPO- and NO-dependent posttranslational modifications at the disease side. We further observed endothelial activation by increased leukocyte adhesion molecule ICAM‑1 staining in aortic root sections of Fbn1 mice but not in Fbn1-DKO mice. Intravital microscopy of cremaster vessels corroborated these findings and showed pronounced leukocyte adhesion and rolling in Fbn1 mice.

Conclusion: We show that the endothelial inflammation and leukocyte adhesion are elevated and driven by MPO in a Marfan mouse model. Locally released MPO causes subsequent activation of matrix-degrading enzymes and tissue remodeling thereby promoting aneurysm formation. Pharmacological inhibition of MPO might represent a novel therapeutic strategy in MFS.