New ways to dismantle a ticking time bomb – miRs-712/-205 and abdominal aortic aneurysm development

Abdominal aortic aneurysms (AAAs) are permanent dilations (> 3cm) of the abdominal aorta that are typically asymptomatic, and the discovery of these potentially deadly vascular lesions is almost always incidental. The most feared clinical consequence of AAA progression is acute rupture, which carries a mortality of 80%, and the number of deaths attributed to AAA rupture is nearly 15,000 annually in the US [1]. However, this number is likely an underestimate since death from AAA rupture may not be readily identified without an autopsy. Sixty percent of patients with AAAs die of other cardiovascular causes, such as myocardial infarction or stroke, suggesting a relationship between AAAs and atherosclerosis. Predictors of AAA growth include diameter of the aorta at diagnosis, advanced age (older than 65), and active smoking [2]. Currently, the only available effective treatment option is surgical repair, either via the traditional open approach, or more commonly, endovascular stenting. Further, neither procedure is employed in the early stages of the disease, and both carry potential operative risks. Even though AAA disease is a common cause of morbidity and mortality in our aging society, it remains a somewhat under-studied disease, with a paucity of information available regarding defined mechanisms of initiation and expansion. Importantly, no pharmacological treatment option has been found to prevent the formation of AAAs or effectively slow the growth of these “ticking time bombs”.

In this dismaying scenario, the discovery of an entirely new method of epigenetic regulation of AAA biology through microRNAs (miRNAs), and their recent validation as potential markers and modulators of pathological conditions, provides new hope for innovative AAA therapy and identification. Inhibition or overexpression of a single miRNA can regulate numerous target genes involved in the coordination of complex pathophysiological processes and disease phenotypes in a wide variety of diseases. Many studies are now beginning to examine the potential of miRNAs as therapeutic and diagnostic entities.

The pathology of AAAs is characterized by progressive aortic dilation, promoted by an imbalance of vascular smooth muscle cell (SMC) apoptosis vs. proliferation, as well as extracellular matrix (ECM) degradation vs. synthesis. This disruption of vessel wall homeostasis is related in large part to localized transmural inflammation [3]. Whereas previous studies on miRNA regulation in AAA disease have mostly focused on their role in SMC apoptosis [4] and protective pro-fibrotic mechanisms in matrix remodeling [5, 6], the manuscript by Kim and colleagues that appears in the current issue of ATVB identifies a novel and crucial role for miR-712 and its human homolog miR-205 in the aortic wall. They demonstrate that the angiotensin II (ANGII)-sensitive miRs-712/-205 target the genes “tissue inhibitor of metalloproteinase-3” (Timp3), and “reversion inducing cysteine-rich protein with kazal motifs” (Reck), which they confirm as important contributors in murine AAA development by controlling aortic metalloproteinase activity and triggering a pro-inflammatory response through downstream ECM degradation in the vessel wall (Figure 1).

Figure 1.

Anti-712/-205 treatment limits murine abdominal aortic aneurysm development through de-repression of Timp3 and Reck.

Abdominal aortic aneurysm = AAA; metalloproteinases = MMP; reversion inducing cysteine-rich protein with kazal motifs = Reck; tissue inhibitor of metalloproteinase-3 = Timp3.

Of importance, they were able to correlate the findings of their experimental animal studies to alterations in miRNA expression in human AAA samples when compared to non-aneurysmal control tissue. While the authors concentrated primarily on the up-regulation of miRs-712/-205 in endothelial cells, there were also significant alterations in the medial layer. In addition, both ANGII and miR-712/-205 manipulation affected circulating leukocyte adhesiveness, further highlighting the therapeutic potential of targeting this pathway and implying other mechanisms at play. Notably, the in silico predicted target Lrp1 was not altered by miR-712/-205 manipulation in the murine model, a common pitfall in microRNA studies. Future studies looking at miR-205 in human tissue will need to verify target regulation, including validated targets such as VEGFA and CTGF (which might well affect AAA biology) [7], and will need to clarify potential interactions with more comprehensive patient clinical characteristics.

Treatment-directed studies utilizing antagomiRs against miR-712 in the ANGII-induced AAA model revealed therapeutic potential for anti-712, limiting AAA development by de-repressing expression levels of Timp3 and Reck. As with other anti-miRNA treatments for cardiovascular disease, potential off-target effects in organ systems that assimilate systemically administered miRNA modulators to a much higher degree (e.g., liver, kidney) would need to be taken into account when developing future therapeutic strategies for AAAs in humans. As with most studies of this sort to date, this work focused primarily on AAA prevention, rather than looking at efficacy in existing aneurysms.

Historically, the murine ANGII AAA model has been used in most studies that examine the therapeutic potential of miRNAs in AAA. The ANGII AAA model has some limitations, and features somewhat unique pathophysiology, including mural disruption and hematoma formation, with aneurysms positioned primarily in the supra-renal abdominal aorta (while human AAA disease is primarily infra-renal). Therefore, translational applicability to human use needs to be viewed with caution. However, the current work of Kim et al. represents an important step towards the eventual goal of defusing these vascular threats.