Abstract 255: Induction of microRNA-21 Inhibits Abdominal Aortic Aneurysm Development and Nicotine-Augmented Expansion
Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRs) are crucial regulators of cardiovascular pathology, and represent possible targets for the inhibition of AAA expansion. We identified miR-21 as a key modulator of proliferation and apoptosis in developing AAA in two established murine models: porcine-pancreatic-elastase, and angiotensin II-infusion. In both models, miR-21 increased with AAA development. Lentiviral overexpression of miR-21 (pre-21) induced cell proliferation and decreased apoptosis in the aortic wall, with protective effects on aneurysm expansion (as shown in Picrosirius Red stained images in the attached Figure below). miR-21 overexpression substantially decreased phosphatase and tensin homolog (PTEN), leading to increased levels of p-AKT, a known pro-proliferative and anti-apoptotic pathway. Systemic injection of a locked-nucleic-acid-modified antagomiR targeting miR-21 (anti-21) diminished the pro-proliferative impact of down-regulated PTEN, leading to significantly increased AAA size as compared to scrambled-control-miR (scr-miR). Importantly, similar results were seen in nicotine-augmented murine AAAs, while parallel findings were observed in human aortic tissue samples from patients undergoing surgical AAA repair (with more pronounced effects in smokers). In vitro studies using human aortic smooth muscle cells, fibroblasts as well as endothelial cells identified NFκB signaling pathways as the key regulator of miR-21 induction. Modulation of miR-21 expression shows great potential as a novel and powerful therapeutic option to limit AAA disease progression.
- © 2012 by American Heart Association, Inc.