Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome.

Abstract

Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGFβ signaling. TGFβ is secreted from cells as a latent complex consisting of TGFβ, the TGFβ propeptide, and a molecule of latent TGFβ binding protein (LTBP). Improper extracellular localization of the latent complex can alter active TGFβ levels, and has been hypothesized as an explanation for enhanced TGFβ signaling observed in MFS. We previously reported the absence of LTBP-3 in matrices lacking fibrillin-1, suggesting that perturbed TGFβ signaling in MFS might be due to defective interaction of latent TGFβ complexes containing LTBP-3 with mutant fibrillin-1 microfibrils. To test this hypothesis, we genetically suppressed Ltbp3 expression in a mouse model of progressively severe MFS. Here, we present evidence that MFS mice lacking LTBP-3 have improved survival, essentially no aneurysms, reduced disruption and fragmentation of medial elastic fibers, and decreased Smad2/3 and Erk1/2 activation in their aortas. These data suggest that, in MFS, improper localization of latent TGFβ complexes composed of LTBP-3 and TGFβ contributes to aortic disease progression.

• Authors: Lior Zilberberg, Colin K L Phoon, Ian Robertson, Branka Dabovic, Francesco Ramirez, Daniel B Rifkin
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 45 Pg. 14012-7 (Nov 10 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26494287 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DNA, Complementary
• Fbn1 protein, mouse
• Fibrillin-1
• Fibrillins
• Latent TGF-beta Binding Proteins
• Ltbp3 protein, mouse
• Microfilament Proteins
• Multiprotein Complexes
• Transforming Growth Factor beta

Topics

• Analysis of Variance
• Animals
• Aortic Aneurysm, Thoracic (etiology, metabolism)
• DNA, Complementary (biosynthesis)
• Fibrillin-1
• Fibrillins
• Immunohistochemistry
• Latent TGF-beta Binding Proteins (deficiency, metabolism)
• Marfan Syndrome (complications, genetics)
• Mice
• Microfilament Proteins (genetics)
• Multiprotein Complexes (metabolism)
• Muscle, Smooth, Vascular (cytology)
• Real-Time Polymerase Chain Reaction
• Transforming Growth Factor beta (metabolism)