Modulating the MicroRNArchitecture of an aging aorta.

The 17th century British physician Thomas Sydenham is credited with saying, “A man is as old as his arteries.” Indeed, aging is associated with myriad structural and functional changes in the cardiovascular system.1 In particular, thoracic aortic aneurysms are commonly found in people during the sixth or seventh decade of life and at a frequency of nearly 1 in 16 000 people per year.2 An aneurysm is a balloon-like bulge that is characterized by thinning and weakness of the vascular wall. Enlarged aortic aneurysms are prone to rupture and often result in death. Maintaining the structural integrity of the aorta is critical to its function and is dictated by the biomechanical properties of the 3 different wall layers: the adventitia, media, and intima. Smooth muscle and extracellular matrix within the media are the largest components of the aortic vascular wall. Smooth muscle cell death or dysfunction and perturbations in extracellular matrix deposition are often associated with aging and aneurysms.3 Advances in surgical procedures to treat aortic aneurysms increase life expectancy and reduce morbidity in the young population but are more risky in the elderly because of cardiovascular comorbidity and surgery-related lethality. Therefore, a comprehensive understanding of the changes in molecular signaling events during aortic aging is necessary to develop novel therapeutics for preventing and treating aneurysm formation. Recent studies have pointed to microRNAs (miRNAs) as key regulators of a variety of cardiovascular disorders and biomarkers of disease progression.4,5 miRNAs negatively regulate target mRNAs through Watson-Crick base pairing with complementary sequences in 3 untranslated regions of mRNAs and often target collections of mRNAs that encode proteins with related functions.6 In this issue of Circulation Research, Stefanie Dimmeler and colleagues provide novel insights into miRNA-mediated pathogenic mechanisms that govern aorta aging.7 Boon et al7 profiled mRNAs and miRNAs in young (6 weeks old) and elderly (18 months old) mouse aortas. They then used 2 independent bioinformatics tools to identify miRNAs whose predicted targets are reciprocally regulated during aging. The only miRNA that met this criterion was miR-29. miR-29 is elevated in old aortas in which extracellular matrix proteins with predicted miR-29 binding sites are decreased. On the basis of these findings, Boon et al7 argued that miR-29 is the only miRNA that significantly affects mRNA expression during aorta aging; this assumes that the bioinformatics algorithms they used accurately predict all miRNA targets. Nonetheless, the authors chose to investigate how miR-29 functions during aortic aging and dilation. The miR-29 family of miRNAs contains 3 members (29a, 29b, and 29c) that are encoded by 2 distinct loci that give rise to bicistronic precursor miRNAs (miR-29a/b1 and miR-29b2/ c). The elevation of miR-29 expression in aged aortas is consistent with a recent report demonstrating that miR-29 is upregulated in multiple tissues during aging and in a progeria mouse model of premature aging.8 Strikingly, the authors observed that only the miR-29a/b1 precursor pri-miRNA was upregulated in aged aortas. This suggests that miR-29c, which is encoded by the miR-29b2/c cluster, must increase via a posttranscriptional mechanism during aging and warrants further investigation. Another unusual finding was that different miR-29 family members displayed distinct patterns of expression in multiple settings of aortic dilation. For example, miR-29a, miR-29b, and miR-29c were all upregulated in aneurysms of fibulin-4 knockout mice, but only miR-29b was elevated after angiotensin II infusion, which causes vascular distention. In addition, miR-29b was the only family member elevated in biopsy samples from patients who displayed thoracic aortic aneurysms. Therefore, it appears as if miR-29b is most sensitive to aortic perturbation. These data suggest that miR-29b is preferentially processed or stabilized during aortic dilation. miR-29 has been shown to regulate extracellular matrix protein levels in multiple cellular contexts.9–12 Indeed, Boon and colleagues7 demonstrated that the mRNAs that encode collagens 1A1 and 3A1 and elastin are all decreased in old aortas. The critical experiment required to transform these phenomenological observations into functionality was performed by blocking miR-29 in angiotensin II–treated mice. Locked nucleic acid–modified 16mer oligonucleotides complementary to miR-29 (anti-miR-29) were used to inhibit miR-29 activity. Anti-miR locked nucleic acids are thought to function by sequestering miRNAs from their mRNA targets.13 The authors demonstrated that all miR-29 family members were reduced in anti-miR-29–treated mice. Importantly, a scrambled locked nucleic acid control, which is often lacking in such studies, was used to confirm specificity. Angiotensin II–treated mice that received anti-miR-29 displayed increases in extracellular matrix gene expression and extraordinary reduction in aorta dilation. It is noteworthy that there were no changes in fibrosis on histological examination. There are several aspects of the study by Boon and colleagues7 that warrant future investigation. First, it is The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX. This manuscript was sent to Ali J. Marian, Consulting Editor, for review by expert referees, editorial decision, and final disposition. Correspondence to Eric N. Olson, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 753909148. E-mail [email protected] (Circ Res. 2011;109:1098-1099.) © 2011 American Heart Association, Inc.