miR-29b Participates in Early Aneurysm Development in Marfan Syndrome

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-␤ (TGF-␤) signaling. Although TGF-␤ blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-␤ 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 B, a repressor of miR-29b, and a factor suppressed by TGF-␤, was also observed in Fbn1 C1039G/؉ aorta. Furthermore, administration of a nuclear factor B inhibitor increased miR-29b levels, whereas TGF-␤ 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:

Emerging Role of MicroRNAs in Cardiovascular Diseases

“…In fact, the selective inhibition of miR-29 with a specific antagonist induced an increase in the expression of matrix proteins, which prevented aneurysm formation both in angiotensin II-induced aneurysm and in genetic models of aneurysm formation. [35][36][37][38][39][40] Despite being modulated in senescent cells and in aged mice, the miR-34 seems to affect age-related disorders in a further way. In fact, its overexpression induces senescence in pro-angiogenic cultured endothelial progenitor cells, 41 and promotes cell death in bone marrow-derived pro-angiogenic cells.…”

Function and Therapeutic Potential of Noncoding RNAs in Cardiac Fibrosis

“…21,22 Anti-miR-mediated inhibition of miR-29 blocked aortic dilation after AngII treatment and significantly reduces abdominal aneurysm formation by an increase in collagen expression. [21][22][23] Although these data support therapeutic use of anti-miR-29 in various vascular indications, and short-term treatment does not appear to induce liver or kidney fibrosis, 21 for more chronic treatment regimes, the potential adverse effects of increasing ECM deposition should be taken into account.…”

Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys–Dietz Syndromes

“…Accordingly, treatment with a miR-29b oligonucleotide inhibitor prevented early formation of aneurysms. 41) Finally, plasma levels of TGF-β, 26) fibrillin-1 fragments, 42) macrophage colony stimulating factor (M-CSF), 21) and oxidative stress indicators 43) have been reported as useful biomarkers for disease progression in humans and animal models. C1039G/+ mice showed significant increases in activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen-activated protein kinase kinase 1 (MEK1), which is the upstream activator of ERK1/2.…”