Abstract 14056: MicroRNA-29 Links Aging with Aortic Aneurysm Formation
Aging is the major risk factor for cardiovascular disease. One particular vascular condition with high mortality is 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). To establish which of these exerts a biological effect in aging, we used two distinct unbiased bioinformatics tools that use mRNA expression data to identify putative regulation by miRNAs. These tools, Sylamer and MirExTra, both 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). The upregulation of the miR-29 family by age was confirmed by real-time PCR. 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. In an experimental mouse model for aneurysm formation, we show that miR-29b, but not miR-29a and c, is induced in the aorta by Angiotensin II, compared to control (1.34-fold ±0.075, p<0.01). Moreover, in human thoracic aneurysm biopsies from patients with biscuspid or triscuspid aortic valves (n=77 and n=30, resp.), miR-29b is also the only miR-29 family member to be regulated (1.86-fold ±0.19, p<0.001 and 1.68-fold ±0.19, p<0.01, resp.), compared to control aorta tissue (n=30). LNA-containing antisense oligonucleotides that silence miR-29 in the aorta in vivo (80–90% knockdown), inhibit one-week Angiotensin II treatment-mediated aorta dilation in apoE−/− mice, as compared to control mice (LNA: 20.7±5.2%, Control: 41.3±7.9%, P<0.01). 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.
- © 2010 by American Heart Association, Inc.