Abstract 14221: Microrna-24 Regulates Inflammation and Calcification During Abdominal Aortic Aneurysm Development Through Targeting Ykl-40
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 intriguing novel targets for the inhibition of AAA expansion. Using microarray as well as qRT-PCR techniques we were able to identify miR-24 as a key modulator of inflammation and calcification in developing AAA in two established murine models: porcine-pancreatic-elastase in male 10 weeks old C57/Bl6 mice, and angiotensin II-infusion in male 10 weeks old apoE-/- mice. In both models, miR-24 downregulation was accompanied by increased expression of YKL-40 (chitinase 3 like-1 = CHI3L1), a newly identified regulator of inflammation and calcification in vascular diseases and rheumatoid arthritis, and a putative target of miR-24. Lentiviral overexpression of miR-24 inhibited YKL-40 induction within the aortic wall, significantly reduced inflammatory activity and macrophage infiltration, and stimulated calcification (indicated by computer tomography determining the aortic calcium score). This was associated with a dramatic decrease in AAA expansion in both mouse models. In contrast, systemic injection of a locked-nucleic-acid-modified antagomiR targeting miR-24 further increased YKL-40 expression, augmented the inflammatory response, and attenuated calcification, with concomitant acceleration of AAA progression. Importantly, similar findings of miR-24 and YKL-40 expression and regulation were observed in human aortic tissue samples from patients undergoing surgical AAA repair (with more pronounced effects in ruptured aortas) as compared to non-dilated control aortas. In vitro studies in human aortic smooth muscle cells, and fibroblasts identified NF-κB signaling as a key modulator of miR-24 regulation. Induction of miR-24 expression shows significant potential as a novel and powerful therapeutic molecular option to limit AAA disease progression by targeting inflammatory and calcific processes in the aortic wall.
- © 2012 by American Heart Association, Inc.