Document Detail


TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome.
MedLine Citation:
PMID:  15546004     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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-beta, and enhanced signaling is a consequence of fibrillin-1 deficiency. We thus hypothesized that increased TGF-beta 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-beta activation and signaling. In addition, TGF-beta antagonism in vivo rescued the valve phenotype, suggesting a cause and effect relationship. Expression analyses identified increased expression of numerous TGF-beta-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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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  114     ISSN:  0021-9738     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-12-03     Completed Date:  2005-02-08     Revised Date:  2014-09-05    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1586-92     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Bone Morphogenetic Proteins / genetics,  metabolism
Disease Models, Animal
Female
Humans
Male
Marfan Syndrome / genetics,  metabolism,  pathology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Microfilament Proteins / genetics,  metabolism*
Mitral Valve / anatomy & histology,  metabolism,  pathology
Mitral Valve Prolapse / genetics,  metabolism*,  pathology*
Phenotype
Pregnancy
Transforming Growth Factor beta / metabolism*
Grant Support
ID/Acronym/Agency:
AR049698/AR/NIAMS NIH HHS; AR41135/AR/NIAMS NIH HHS; HL067056/HL/NHLBI NIH HHS; HL53325/HL/NHLBI NIH HHS; K08 HL067056/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Bone Morphogenetic Proteins; 0/Microfilament Proteins; 0/Transforming Growth Factor beta; 0/fibrillin
Comments/Corrections
Comment In:
J Clin Invest. 2004 Dec;114(11):1543-6   [PMID:  15578086 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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