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

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. IntroductionMarfan syndrome (MFS) is a common, autosomal-dominant, systemic disorder of connective tissue, with an estimated prevalence of 1 in 5,000-10,000 individuals (1). It is caused by mutations in FBN1, the gene encoding fibrillin-1 (2), the principal component of extracellular matrix microfibrils. Clinical manifestations of MFS include skeletal deformities, ocular lens dislocation, lung pathology, and cardiac complications, such as aortic dissection and mitral valve prolapse (MVP) and dysfunction. Mitral valve disease is the leading indication for surgery and cause of death in young children with MFS, and there are currently no known or proposed medical therapies for prophylactic treatment of valve disease. While infants presenting with the most severe and rapidly progressive form of MFS can show mitral valve dysfunction at birth, manifestations are highly variable in the classic form of MFS, and myxomatous changes are not easily quantified using noninvasive imaging modalities, precluding a precise understanding of the natural history of disease. To our knowledge, neither recapitulation nor mechanistic exploration of mitral valve pathology in mouse models of MFS has previously been documented.

Induction and Coexpression of Latent Transforming Growth Factor β-Binding Protein-1 and Fibrillin-1 in Experimental Glomerulonephritis

“…Our findings in the glomerulus extend that obtained in other tissues to the renal mesangium and glomerular disease. Whether or not the induction of LTBP-1 and fibrillin-1 has a beneficial effect for the course of anti-Thy1.1 glomerulonephritis is still unclear, but recent data suggest that the interaction of LTBP-1 and fibrillin-1 plays an important role in the regulation of TGF-β activation [4, 5]. …”

“…LTBP-1 and fibrillin-1 are highly homologous molecules and have been shown to colocalize and interact in the extracellular matrix of these tissues [3]. The interaction of LTBP-1 and fibrillin-1 seems to be important for the stabilization of latent TGF-β complexes in the extracellular matrix [4]. In fibrillin-1-deficient mice, activation of TGF-β was recently described [5].…”

Marfan syndrome and mitral valve prolapse

“…In a study reported in this issue of the JCI, Ng et al tested the hypothesis that the fibrillin-1-TGF-β pathway is implicated in the pathogenesis of MVP in a murine model of Marfan syndrome (26). They compared the morphometry of mitral valves in fibrilin-1-deficient mice to those of wild-type mice and report a progressive increase in leaflet length and thickness in heterozygous versus homozygous mice.…”

“…The most significant morphologic changes were noted in the homozygous mice. While homozygous and dual heterozygous forms of FBN1 mutations in children have been reported, they appear to be lethal at an early age (30), as was the case in the homozygous mice in the Ng et al study (26), and thus the homozygous model may be less applicable to the evolution of the human disease. Second, although the histology of the valves in this study is not described in detail, the hypercellularity of the leaflets is striking.…”

“…The finding that TGF-β dysregulation in the connective tissue plays an important role in the development of prolapse in Marfan syndrome (26) raises the question as to whether this cytokine may play a role in other forms of prolapse, including sporadic MVP. It has been suggested that the altered extracellular matrix in fibrillin-1-deficient mice cues cells to In patients with MVP, myxomatous degeneration of the leaflets and chordae results in leaflet thickening and redundancy, causing the leaflets to prolapse, or flop backwards, into the left atrium (detail).…”