Programmheft

Sitzung

261
Freie Mitteilungen 3
4. November 2022, 11:00 - 12:00, Gartensaal 2

Abstract

New options to treat Marfan disease
N. Rosenblatt-Velin, Presenter: N. Rosenblatt-Velin (Lausanne)

Objective
Marfan Syndrome (MFS) is an autosomal dominant inherited connective tissue disorder affecting the cardio-vascular system. Aortic dissections and ruptures are the primary cause of morbidity and mortality in these patients. No treatment really cures Marfan patients. Interestingly, in humans, mutations in the gene coding for the C-type natriuretic peptide (CNP) or its receptors lead to a “Marfan-like syndrome”. CNP is a local regulator of skeletal growth and of vascular homeostasis, remodeling and angiogenesis. CNP binds to two receptors, NPR-B and NPR-C, expressed on endothelial and smooth muscle cells (SMCs). The aim of this project is to determine whether altered CNP signaling pathway contributes to the development and progression of the vascular dysfunctions in MFS.
Methods
Plasma and vessel biopsies were taken from Marfan patients and from Fbn1C1039G/+ mice. CNP and TGF-beta concentrations were measured in the plasma. CNP, NPR-B and NPR-C protein levels were evaluated by Western blot analysis in aortic tissue during the development of MFS.
Results
CNP plasma concentration was decreased in Marfan patients compared to age and sex-matched non-Marfan patients (18 pmol/l versus 310; p=0.07). Two fold less CNP protein level was detected in the abdominal aorta of a Marfan patient. In 6-7 week-old male Fbn1 +/- mice, CNP mRNA and protein levels were drastically decreased in the aortic arch and ascending aorta and increased in the descending aorta. In 24 week-old Marfan male mice, CNP protein level was normalized in the different segments of the aorta. In the aortic arch and ascending aorta of female Fbn1 +/- mice, CNP mRNA and protein levels didn't change in young animals (6 weeks old) but increased in 24-week-old mice. NPR-C protein levels were decreased in the aortic arch and ascending aorta in male and female mice during the development of the Marfan disease. NPR-B protein level remained unchanged.
Conclusion
Male mice develop a more severe disease than female mice. Our results suggest that a deficit in CNP could contribute to the development and progression of the disease in male mice. In contrast, in female mice, normal and higher CNP levels could protect from the progression of the MFS. If the role of CNP is confirmed in the development and progression of the MFS, these results will open the door to new therapies for Marfan patients.
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