Mr Lars Maegdefessel
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List of Authors: Lars Maegdefessel (1,2), Uwe Raaz (1), Joshua M. Spin (1), Per Eriksson (2), Anders Hamsten (2), Philip S. Tsao (1)
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 fibrosis 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 tissue remodeling 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 tissue remodeling. This was associated with a dramatic decrease in AAA expansion in both mouse models. In contrast, systemic injection of a lentiviral vector carrying an antagomiR targeting miR-24 further increased YKL-40 expression, augmented the inflammatory response, and attenuated fibrosis, 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 as compared to non-dilated control aortas. Furthermore, YKL-40 plasma levels were substantially increased in patients with AAA compared to control patients with a significant further increase in patients with large AAA compared to smaller AAA. In vitro studies in human aortic smooth muscle cells and macrophages identified NF-κB signaling as a key regulator of miR-24 expression. Counteracting miR-24 downregulation shows great potential as a novel and powerful therapeutic option to limit AAA disease progression by targeting inflammatory and tissue remodeling processes in the aortic wall. Furthermore, YKL-40 appears as an intriguing novel biomarker to identify human AAA disease severity.
1:Stanford University, Stanford, CA (USA), Division of Cardiovascular Medicine2:Karolinska Institute, Stockholm (Sweden), Department of Medicine, Atherosclerosis Research Unit
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