title: miR-29b participates in early aneurysm development in Marfan syndrome.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, 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.
authors: Department of Cardiothoracic Surgery, 300 Pasteur Drive, Falk Cardiovascular Research Building, Stanford University, Stanford, CA 94305, USA.
authors: Denis R
authors: DR
authors: Merk
authors: Jocelyn T
authors: JT
authors: Chin
authors: Benjamin A
authors: BA
authors: Dake
authors: Lars
authors: L
authors: Maegdefessel
authors: Miquell O
authors: MO
authors: Miller
authors: Naoyuki
authors: N
authors: Kimura
authors: Philip S
authors: PS
authors: Tsao
authors: Cristiana
authors: C
authors: Iosef
authors: Gerald J
authors: GJ
authors: Berry
authors: Friedrich W
authors: FW
authors: Mohr
authors: Joshua M
authors: JM
authors: Spin
authors: Cristina M
authors: CM
authors: Alvira
authors: Robert C
authors: RC
authors: Robbins
authors: Michael P
authors: MP
authors: Fischbein
mesh_terms: D000367:Age Factors; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001014:Aortic Aneurysm / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D015316:Genetic Therapy / Q000379:methods; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008382:Marfan Syndrome / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D054392:Adipokines
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D051017:Apoptosis Regulatory Proteins; D004549:Elastin; D000071838:Fibrillin-1; D000071837:Fibrillins; D019808:Losartan; D020778:Matrix Metalloproteinase 2; D035683:MicroRNAs; D008840:Microfilament Proteins; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D016212:Transforming Growth Factor beta; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C547014:MIRN29 microRNA, mouse; C522362:Mmp2 protein, mouse