Abstract 16050: Microrna-21 Regulates Expansion of Abdominal Aortic Aneurysms Through the PTEN/PI3K/AKT Pathway
Successful identification, treatment, and limitation of abdominal aortic aneurysm (AAA) disease remain some of the biggest challenges in modern vascular medicine. The discovery that microRNAs (miRs) serve as crucial regulators of pathologic processes in the cardiovascular system hint at novel potential approaches to understanding and treating AAAs. We identified miR-21 as a key modulator of proliferation, migration, apoptosis, and inflammation in developing AAAs in two different mouse models of aneurysm disease, the porcine-pancreatic-elastase model in C57Bl/6 mice, and the angiotensin II-infusion model in apoE-/- mice. AAA development resulted in increased miR-21, and substantially decreased expression of its target ‘phosphatase and tensin homolog’ (PTEN) at different time points during aneurysm development in both experimental models. This was associated with increased levels of downstream phosphatidylinositol 3-kinase (PI3K) and AKT, elements of a known pro-proliferative and anti-apoptotic pathway. Systemic injection of a locked-nucleic-acid (LNA) modified antagomir targeting miR-21 blunted both the PTEN decrease and its pro-proliferative effects, and led to a significant increase in AAA diameter as detected by B-mode ultrasound imaging (Figure 1). Overexpression of miR-21 with a pre-miR carrying lentivirus further downregulated PTEN and had a significant protective effect on aneurysm expansion, inducing massive aortic smooth muscle and fibroblast proliferation compared to scrambled-control-miR. Up-regulated miR-21 and down-regulated PTEN were also reproducibly observed in aortic samples obtained from human patients (n=10) undergoing surgical AAA repair when compared to a control group of organ donors without AAA (n=7). Modulation of miR-21 expression may become a powerful therapeutic option in limiting AAA disease progression and complications.
- © 2011 by American Heart Association, Inc.