Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome.
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.
Department of Cell Biology, New York University School of Medicine, New York, NY 10016; zilbel01@med.nyu.edu.
Lior
L
Zilberberg
Division of Pediatric Cardiology, Department of Pediatrics, New York University School of Medicine, New York, NY 10016;
Colin K L
CK
Phoon
Department of Cell Biology, New York University School of Medicine, New York, NY 10016;
Ian
I
Robertson
Department of Cell Biology, New York University School of Medicine, New York, NY 10016;
Branka
B
Dabovic
Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029;
Francesco
F
Ramirez
Department of Cell Biology, New York University School of Medicine, New York, NY 10016; Department of Medicine, New York University School of Medicine, New York, NY 10016.
Daniel B
DB
Rifkin
D000704:Analysis of Variance; D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000209:etiology / Q000378:metabolism*; D018076:DNA, Complementary / Q000096:biosynthesis; D000071838:Fibrillin-1; D000071837:Fibrillins; D007150:Immunohistochemistry; D053779:Latent TGF-beta Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D008382:Marfan Syndrome / Q000150:complications* / Q000235:genetics*; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics; D046912:Multiprotein Complexes / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D060888:Real-Time Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054392:Adipokines
D018076:DNA, Complementary; D000071838:Fibrillin-1; D000071837:Fibrillins; D053779:Latent TGF-beta Binding Proteins; D008840:Microfilament Proteins; D046912:Multiprotein Complexes; D016212:Transforming Growth Factor beta; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C509039:Ltbp3 protein, mouse
LTBP; aneurysm; extracellular matrix; transforming growth factor beta