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miR-29b Participates in Early Aneurysm Development in Marfan Syndrome.
MedLine Citation:
PMID:  22116819     Owner:  NLM     Status:  Publisher    
Rationale:Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-β (TGF-β) signaling. Although TGF-β blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-β causes aneurysms remain ill-defined.Objective:We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS.Methods and Results:Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition gene, is increased in the ascending aorta of Marfan (Fbn1(C1039G/+)) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1(C1039G/+) aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1(C1039G/+) ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor κB, a repressor of miR-29b, and a factor suppressed by TGF-β, was also observed in Fbn1(C1039G/+) aorta. Furthermore, administration of a nuclear factor κB inhibitor increased miR-29b levels, whereas TGF-β blockade or losartan effectively decreased miR-29b levels in Fbn1(C1039G/+) mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies.Conclusions:We identify increased miR-29b expression as key to the pathogenesis of early aneurysm development in MFS by regulating aortic wall apoptosis and extracellular matrix abnormalities.
Denis R Merk; Jocelyn T Chin; Benjamin A Dake; Lars Maegdefessel; Miquell O Miller; Naoyuki Kimura; Philip S Tsao; Cristiana Iosef; Gerald J Berry; Friedrich W Mohr; Joshua M Spin; Cristina M Alvira; Robert C Robbins; Michael P Fischbein
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-11-23
Journal Detail:
Title:  Circulation research     Volume:  -     ISSN:  1524-4571     ISO Abbreviation:  -     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Cardiothoracic Surgery, Department of Pediatrics, Department of Cardiovascular Medicine, Department of Pathology, Stanford University, Stanford, CA; Department of Cardiothoracic Surgery, Heart Center Leipzig, Leipzig, Germany.
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