Abstract 11721: MicroRNA-29 in Aortic Aneurysm Formation
Aging is the major risk factor for aortic aneurysm formation and subsequent rupture. MicroRNAs (miRNAs) have recently emerged as key biological regulators. To study the role of miRNAs in aging of the aorta we generated miRNA and mRNA microarray expression profiles comparing aged (18 months old) with young mice (6 weeks old). We identified 20 miRNAs that are regulated by age (fold change>1.5, p<0.01). Using the bioinformatics tools, Sylamer and MirExTra, we identified the miR-29 family (miR-29a, b and c) to be the only one of the 20 regulated miRNAs to functionally affect mRNA levels (p<0.001). Known targets of miR-29 include many collagen genes, fibrillin and elastin and these were also downregulated by age in the aorta (−1.56 to −4.73-fold, p<0.01). We hypothesized that age-induced miR-29 inhibits extracellular matrix (ECM) deposition, thereby making the aorta more susceptible for aneurysm formation. Indeed, miR-29 is induced in the aorta of two mouse models for aneurysm formation (Fibulin-4 mutant and AngII infusion, 2.5-fold, p<0.05 and 1.34-fold, p<0.01, resp). Moreover, in a large cohort of human thoracic aneurysm biopsies, miR-29 is robustly upregulated, compared to control aorta tissue (1.86-fold, p<0.001, n=107). Mechanistically, miR-29 is predominantly expressed in vascular smooth muscle cells, but also present in endothelial cells, and expressional regulation occurs through the Notch and TGF-beta signaling cascades. LNA-containing antisense oligonucleotides that silence miR-29 in the aorta in vivo, induce the expression of collagens and elastin (1.65 to 2.05-fold, p<0.05). Accordingly, Angiotensin II-mediated aorta dilation in vivo (104±18.6 µm increase in diameter) was completely halted by silencing miR-29. In conclusion, induction of miR-29 by age and concomitant downregulation of ECM proteins in the aorta could cause the formation of aneurysms and inhibition of miR-29 attenuates experimental aneurysm formation in mice, which provides a novel molecular target to avert aneurysm formation.
- © 2011 by American Heart Association, Inc.