Signature Protein Profiles to Identify Disease Progression and Therapeutic Modification in Murine and Human Models of Aortic Abdominal Aneurysms
Final Report Abstract
Identification and treatment of abdominal aortic aneurysm (AAA) disease remain among the most prominent challenges in modern vascular medicine. MicroRNAs (miRs) have been identified as crucial regulators of cardiovascular pathology, and represent novel therapeutic targets for a potential inhibition of AAA expansion. By using microarray as well as qrt-PCR techniques, we identified miRs-21 and -29b as key modulators of proliferation, apoptosis, and fibrosis in developing AAAs in two murine models. miR-21 levels increased with AAA development, and substantially decreased expression of the phosphatase and tensin homolog (PTEN) gene during aneurysm development in both experimental models, resulting in increased levels of p-AKT, a pathway known to exert proproliferative and anti-apoptotic effects in various cell types. Increases in Col1a1, Col3a1, Col5a1, and Eln with AAA development, were accompanied by decreased miR-29b expression in both models. In vivo administration of a locked-nucleic-acid (LNA) antagomiR against miR-29b greatly increased collagen gene expression, leading to an early fibrotic response in the abdominal aortic wall (vs. a scrambled-control-miR), and resulting in a significant reduction of abdominal aortic diameter progression over time. Overexpression of miR-21, using a lentiviral vector, as well inhibited AAA expansion by increasing proliferation and decreasing apoptosis, most prominently in vascular smooth muscle cells and fibroblasts. A similar pattern of miR-21 and miR-29b and their target gene regulation was observed in human aortic tissue samples from patients undergoing surgical AAA repair when compared with aortic tissue samples from organ donor controls. In vitro experiments utilizing human aortic smooth muscle cells, fibroblasts, as well as endothelial cells identified NFκB as the key regulator of miR-21 - and TGFβ as the main modulator of miR-29b expression. Regulation of the identified miRs as well as their target genes represents a potential new therapy on a molecular basis to limit AAA disease progression and protection from rupture.
Publications
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Assessment of elastase-induced murine abdominal aortic aneurysms: comparison of ultrasound imaging with in situ video microscopy. J Biomed Biotechnol. 2010:25:21-41
Azuma J, Maegdefessel L, Kitagawa T, Dalman RL, McConnell MV, Tsao PS
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MicroRNA-26a is a novel regulator of vascular smooth muscle cell function. J Cell Physiol. 2010;226(4):1035-43
Leeper NJ, Raiesdana A, Kojima Y, Chun HJ, Azuma J, Maegdefessel L, Kundu RK, Quertermous T, Tsao PS, Spin JM
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Influences of aortic motion and curvature on vessel expansion in murine experimental aneurysms. Arterioscler Thromb Vasc Biol. 2011;31(2):27-9
Goergen CJ, Azuma J, Barr KN, Magdefessel L, Kallop DY, Gogineni A, Grewall A, Weimer RM, Connolly AJ, Dalman RL, Taylor CA, Tsao PS, Greve JM
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miR-29b Participates in Early Aneurysm Development in Marfan Syndrome. Circ Res. 2011 Nov 23. [Epub ahead of print]
Merk DR, Chin JT, Dake BA, Maegdefessel L, Miller M, Kimura N, Tsao PS, Spin JM, Mohr FW, Robbins RC, Fischbein MP
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Transcriptional profiling and network analysis of the murine angiotensin II-induced abdominal aortic aneurysm. Physiol Genomics. 2011:43:993-1003
Spin JM, Hsu M, Azuma J, Tedesco MM, Dyer JS, Maegdefessel L, Dalman RL, Tsao PS
