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Posttranslational modifications in Marfan’s disease mediated by myeloperoxidase

Marfan Syndrome (MFS) represents one of the most prevalent autosomal-dominant hereditary connective-tissue disorders and is caused by mutations in the fibrillin-1 gene (Fbn1). Affected patients develop varying patterns of organ malfunction, including ocular, skeletal, pulmonary, and dermatological manifestations, with thoracic aortic aneurysm (TAA) and aortic dissection being the most common causes of death. Within the aortic wall the Fbn1 mutation provokes an increased abundance of the extracellular matrix (ECM)-sequestered transforming growth factor ß (TGF-ß). Aberrantly increased bioavailability of TGF-ß drives proinflammatory and pro-oxidant signaling pathways in smooth muscle cells (SMC) and switches on gene transcription, which destabilizes the elastic-fiber scaffold of the vessel wall. Notably, TGF-ß is also a central messenger that activates the innate and adaptive immune systems by using MAP-kinase-signaling and phosphorylation of SMAD2/3. At the same time, accumulating evidence suggests that innate immune responses indeed critically contribute to disease progression in MFS. Polymorphonuclear neutrophils (PMN) represent the main cellular effectors of the innate immune system and carry a diverse armament of tissue-degrading enzymes. Myeloperoxidase (MPO), a heme-containing protein, which is encapsulated in the azurophilic granules of the neutrophil and released upon PMN activation, represents one of its most abundant proteins.

Herein, we seek to investigate the role of leukocyte-derived MPO in the pathogenesis of MFS. MPO has been shown to critically affect endothelial and vascular SMC (VSMC) function: Following secretion by PMN and to a lesser extent by monocytes, MPO enters the subendothelial space, where it oxidizes nitric oxide (NO), thus impairing the humoral integrity of the vessel. Vascular MPO deposition also accounts for maladaptive endothelial glycocalyx remodeling leading to enhanced leukocyte recruitment. In addition, MPO affects the phenotype of SMCs, with structural vascular remodeling seen as a consequence in various pathological settings.
Moreover, MPO has been shown to directly activate matrix-metalloproteinases (MMPs), which in turn degrade matrix proteins including elastin and collagens. In addition, we recently identified MPO as a potent inducer of fibroblast-to-myofibroblast transdifferentiation by activating MAP-kinase pathways, altogether these data support the hypothesis that MPO has a role in affecting the structural integrity of the vessel.

We hypothesize that activation of neutrophils and release of MPO adversely affects vascular signaling and thus aggravates aneurysm formation in MFS.

We plan to elucidate the role of MPO in vascular remodeling in MFS. In Aim 1, we will characterize the vascular phenotype in two murine MFS models, with a particular focus on the contributory role of MPO. Here, we will characterize the extent and mechanisms of PMN activation and the binding of MPO to the aorta. Aim 2 will focus on the consequences of MPO deposition in the vessel wall and dissect the effects of MPO on NO bioavailability and endothelial function. Aim 3 will analyze the role and mechanisms of posttranslational ECM modification by MPO in the vessel. Aim 4 plans to test the pharmacological inhibition of MPO using a specific orally applicable inhibitor in Fbn1+/C1039G mice. In summary, this project aims to uncover the role of the innate immune system in MFS and will define the interplay between ECM proteins, matrix-degrading enzymes, and the role of MPO in MFS-related aortic disease, such as aneurysm formation. In a potential subsequent funding period, we propose to test the role of MPO in the development of aortic stenosis and the effect of the pharmacological inhibition of MPO for the development of aortic aneurysm formation and aortic stenosis.



A04 Hypothesis: Release of MPO and binding to the vessel wall critically affects matrix remodeling in Marfan syndrome.

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