NEW YORK (Reuters Health) - A common abnormality in Marfan syndrome is mitral valve prolapse. In a murine model of the syndrome, excess activation of transforming growth factor (TGF)-beta associated with fibrillin-1 mutations appears to be responsible for the myxomatous changes in the mitral valves, new research shows.
Little is known about the pathogenetic sequence that leads to mitral valve disease, Dr. Daniel P. Judge, at Johns Hopkins University School of Medicine in Baltimore, and his team note in their report, published in the Journal of Clinical Investigation for December 1st.
Marfan syndrome is caused by mutations in FBN1, the gene that encodes fibrillin-1, the authors note, and fibrillin-1 is known to regulate TGF-beta activation. As a model of Marfan syndrome, as well as acquired myxomatous mitral valve disease, the authors created a mouse line harboring Fbn1 mutations.
Fibrilin-1-deficient mice showed increased mitral valve leaflet length and thickness. By 9 months of age, mitral valve prolapse and regurgitation had occurred.
Using monoclonal antibody against the free and active form of TGF-beta, the researchers observed increased immunoactivity in the valve leaflets of the mutant animals, but no increase in the latent form of the cytokine, “indicative of increased TGF-beta activation rather than cytokine production.”
When antibody was administered to pregnant mice, valve leaflet length and thickness were decreased in the offspring.
“These data demonstrate a role for TGF-beta as a physiologic regulator of mitral valve morphology and support a causal relationship between TGF-beta dysregulation and mitral valve disease in Marfan syndrome,” Dr. Judge’s group writes.
They observed increased expression of several effector molecules downstream of TGF-beta signaling, including TGF-beta-inducible gene H3, endothelin-1, tissue inhibitor of metalloproteinase 1, and bone morphogenetic proteins, “genes that regulate cell proliferation and survival and plausibly contribute to myxomatous valve disease.”
These findings were reinforced by the authors’ observation of increased cell proliferation and decreased apoptosis in fibrillin-1-deficient mice compared with wild-type valves.
“This work provides a novel context within which to further explore the pathogenesis of acquired myxomatous degeneration of the mitral valve in both Marfan syndrome and more common, non-syndromic variants of the disease,” the authors conclude.
In a related editorial, however, Drs. Arthur E. Weyman and Marielle Scherrer-Crosbie, at Massachusetts General Hospital in Boston, point out that mitral valve alterations in Marfan syndrome differ from those observed in human acquired myxomatous mitral valve disease. For example, abnormalities in FBN1 have not been observed in sporadic disease, and severe mitral valve disorders are generally manifest in adults, not infants.
Thus, they maintain, “A great deal of study remains necessary before the pathogenic mechanisms underlying idiopathic Marfan syndrome and its relationship to more generalized forms of connective tissue disease are clarified.”
Source: J Clin Invest 2004;114:1543-1546,1586-1592. [ Google search on this article ]
MeSH Headings:Enzyme Inhibitors: Enzymes, Coenzymes, and Enzyme Inhibitors: Protease Inhibitors: Transforming Growth Factors: Tissue Inhibitor of Metalloproteinases: Chemical Actions and Uses: Chemical Actions: Chemicals and DrugsCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
