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TGF-β–dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome
Connie M. Ng, … , Daniel P. Judge, Harry C. Dietz
Connie M. Ng, … , Daniel P. Judge, Harry C. Dietz
Published December 1, 2004
Citation Information: J Clin Invest. 2004;114(11):1586-1592. https://doi.org/10.1172/JCI22715.
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Article Cardiology Article has an altmetric score of 7

TGF-β–dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome

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Abstract

Mitral valve prolapse (MVP) is a common human phenotype, yet little is known about the pathogenesis of this condition. MVP can occur in the context of genetic syndromes, including Marfan syndrome (MFS), an autosomal-dominant connective tissue disorder caused by mutations in fibrillin-1. Fibrillin-1 contributes to the regulated activation of the cytokine TGF-β, and enhanced signaling is a consequence of fibrillin-1 deficiency. We thus hypothesized that increased TGF-β signaling may contribute to the multisystem pathogenesis of MFS, including the development of myxomatous changes of the atrioventricular valves. Mitral valves from fibrillin-1–deficient mice exhibited postnatally acquired alterations in architecture that correlated both temporally and spatially with increased cell proliferation, decreased apoptosis, and excess TGF-β activation and signaling. In addition, TGF-β antagonism in vivo rescued the valve phenotype, suggesting a cause and effect relationship. Expression analyses identified increased expression of numerous TGF-β–related genes that regulate cell proliferation and survival and plausibly contribute to myxomatous valve disease. These studies validate a novel, genetically engineered murine model of myxomatous changes of the mitral valve and provide critical insight into the pathogenetic mechanism of such changes in MFS and perhaps more common nonsyndromic variants of mitral valve disease.

Authors

Connie M. Ng, Alan Cheng, Loretha A. Myers, Francisco Martinez-Murillo, Chunfa Jie, Djahida Bedja, Kathleen L. Gabrielson, Jennifer M.W. Hausladen, Robert P. Mecham, Daniel P. Judge, Harry C. Dietz

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Figure 1

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Histologic and morphometric assessment of mitral valve architecture in P...
Histologic and morphometric assessment of mitral valve architecture in P6.5 mice. Fbn1 genotypes are indicated as follows: +/+ (Fbn1+/+), +/− (Fbn1C1039G/+), and −/− (Fbn1C1039G/C1039G). (A) Representative mitral valve sections from each genotype at P6.5 showing increased length and thickness in mutant valves as compared to wild-type littermates. Magnification, ×20. Scale bars: 100 μm. (B) Morphometric analysis of mitral valve length during the first week of postnatal life. Fbn1C1039G/C1039G valves were significantly longer by P6.5 when compared with those of Fbn1+/+ animals (–;P –; 0.05). (C) Morphometric analysis of mitral valve thickness during the first week of postnatal life. Increased valve thickness in Fbn1C1039G/C1039G versus Fbn1+/+ mice was significant by P4.5 (*P –; 0.005 vs. Fbn1+/+), and by P6.5, differences between all genotypes were statistically significant (*P –; 0.005 vs. Fbn1+/+; –;P –; 0.05 vs. Fbn1C1039G/+). Error bars indicate 95% confidence intervals. (D) Echocardiographic parasternal long axis views of 9-month Fbn1C1039G/+ and Fbn1+/+ mouse hearts. The anterior mitral valve leaflet (arrowhead) shows increased length and thickening, as well as systolic prolapse into the LA in fibrillin-1–;deficient mice. AoR, aortic root; AscAo, ascending aorta; LA, left atrium.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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