| First Author | Merk DR | Year | 2012 |
| Journal | Circ Res | Volume | 110 |
| Issue | 2 | Pages | 312-24 |
| PubMed ID | 22116819 | Mgi Jnum | J:192708 |
| Mgi Id | MGI:5466232 | Doi | 10.1161/CIRCRESAHA.111.253740 |
| Citation | Merk DR, et al. (2012) miR-29b participates in early aneurysm development in Marfan syndrome. Circ Res 110(2):312-24 |
| abstractText | 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-beta (TGF-beta) signaling. Although TGF-beta blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-beta 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 kappaB, a repressor of miR-29b, and a factor suppressed by TGF-beta, was also observed in Fbn1(C1039G/+) aorta. Furthermore, administration of a nuclear factor kappaB inhibitor increased miR-29b levels, whereas TGF-beta 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. |
