MiR-29b participates in early aneurysm development in Marfan syndrome

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

Research output: Contribution to journalArticlepeer-review

143 Scopus citations

Abstract

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 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 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.

Original languageEnglish (US)
Pages (from-to)312-324
Number of pages13
JournalCirculation research
Volume110
Issue number2
DOIs
StatePublished - Jan 20 2012
Externally publishedYes

Keywords

  • aneurysm
  • apoptosis
  • extracellular matrix
  • Marfan syndrome
  • microRNA

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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