Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development
Lars Maegdefessel, … , Joshua M. Spin, Philip S. Tsao
Lars Maegdefessel, … , Joshua M. Spin, Philip S. Tsao
Published January 24, 2012
Citation Information: J Clin Invest. 2012;122(2):497-506. https://doi.org/10.1172/JCI61598.
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Research Article

Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development

Abstract

MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe–/– mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti–miR-29b greatly increased collagen expression, leading to an early fibrotic response in the abdominal aortic wall and resulting in a significant reduction in AAA progression over time in both models. In contrast, overexpression of miR-29b using a lentiviral vector led to augmented AAA expansion and significant increase of aortic rupture rate. Cell culture studies identified aortic fibroblasts as the likely vascular cell type mediating the profibrotic effects of miR-29b modulation. A similar pattern of reduced miR-29b expression and increased target gene expression was observed in human AAA tissue samples compared with that in organ donor controls. These data suggest that therapeutic manipulation of miR-29b and its target genes holds promise for limiting AAA disease progression and protecting from rupture.

Authors

Lars Maegdefessel, Junya Azuma, Ryuji Toh, Denis R. Merk, Alicia Deng, Jocelyn T. Chin, Uwe Raaz, Anke M. Schoelmerich, Azad Raiesdana, Nicholas J. Leeper, Michael V. McConnell, Ronald L. Dalman, Joshua M. Spin, Philip S. Tsao

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Figure 5

Fibrosis in miR-29b–modulated mice with PPE-induced AAAs.

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Fibrosis in miR-29b–modulated mice with PPE-induced AAAs. (A) Representa...
(A) Representative polarized light microscopy of picrosirius red–stained aortic cross sections (original magnification, ×40), illustrating aneurysm expansion and fibrosis (collagen fibers are bright yellow) in sham, scr-miR, and anti- and pre-29b mice 28 days after AAA induction with PPE. (B) Representative Col3a1 immunohistochemical images, demonstrating effects of pre-29b, scr-miR, and anti-29b 14 days after AAA induction with PPE (original magnification, ×200). (C) Quantification of Col3a1-positive cells in the intima/media region (n = 4 high-power fields of 3 different aortas per group) 14 days after AAA induction with PPE. (D) In situ zymography images to detect MMP activity in scr-miR– and anti- and pre-29b–transduced aortas 14 days after PPE-induced AAA in mice (original magnification, ×200). (E) Mmp2 and (F) Mmp9 expression in miR-29b–modulated mice with PPE-induced AAA (after 14 days). n = 4–8 mice per treatment group. Data are mean ± SEM. *P < 0.05 versus sham. #P < 0.05 versus scr-miR and anti-29b or pre-29b.