Clin Res Cardiol 101, Suppl 1, April 2012

V127 - Induction of microRNA-21 by NFκB inhibits abdominal aortic aneurysm development and nicotine-augmented expansion
L. Maegdefessel1, J. Azuma1, R. Toh1, D. R. Merk2, A. Deng1, U. Raaz1, A. Raiesdana1, N. Leeper3, M. McConnell1, R. Dalman3, J. Spin1, P. S. Tsao1
1Division of Cardiovascular Medicine, Stanford University, Stanford, USA; 2Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, USA; 3Division of Vascular Surgery, Stanford University, Stanford, USA;
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 induced cell proliferation and decreased apoptosis in the aortic wall, with protective effects on aneurysm expansion. 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 diminished the pro-proliferative impact of down-regulated PTEN, leading to significantly increased AAA size. 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 in 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 potential as a novel and powerful therapeutic option on a molecular basis to limit AAA disease progression.
Clin Res Cardiol 101, Suppl 1, April 2012
Zitierung mit Vortrags- oder Posternummer s.o.
DOI 10.1007/s00392-012-1100-6