Nicotine and miR-24 in abdominal aortic aneurysm
Final Report Abstract
miR-24 project: Using two established murine AAA models, we identified miR-24 as a key regulator of inflammation and AAA initiation and propagation in vivo and in vitro. MiR-24 acts in part by targeting Chi3l1, an effector regulating cytokine synthesis in macrophages as well as their survival and affecting aortic smooth muscle cell and endothelial cell activation. miR-24 modulation in vivo alters AAA progression and miR-24 and CHI3L1 represent novel potential biomarkers for AAA disease progression. Additionally, we could show that, nicotine further down-regulates the anti-inflammatory microRNA miR-23b/24/27b family within the aortic wall beyond that already noted during AAA formation. Nicotine also downregulates miR-24-1 and augments IL6-induced repression of miR-24-1 in macrophages. Furthermore, nicotine increases expression of the miR-24- regulated cytokine CHIL1/CHI3L1. miR-223 project: We could show that an early increase of miR-223 in vivo is an important mechanism in AAA initiation and progression. miR-223 enhances differentiation, activation, survival and recruitment of M1 macrophages in vitro and in vivo. By preventing this early increase of miR- 223 in vivo with application of anti-miR-223 we could mitigate macrophage infiltration and, thereby, almost completely inhibit AAA formation. We propose a mechanism, in which inhibition of DUSP10, a MAPK-phosphatase, leads to increased P38-activation and subsequently upregulates cytokine production of IL-1b, MCP-1 and MCP-3. This drives macrophage recruitment and pro-inflammatory differentiation thereby mediates a more pronounced inflammatory reaction in AAA tissue.
Publications
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MiR-24 limits aortic vascular inflammation and murine abdominal aneurysm development. Nat Commun. 2014 Oct 31;5:5214
Maegdefessel L, Spin JM, Raaz U, Eken SM, Toh R, Azuma J, Adam M, Nagakami F, Heymann HM, Chernugobova E, Jin H, Roy J, Hultgren R, Caidahl K, Schrepfer S, Hamsten A, Eriksson P, McConnell MV, Dalman RL, Tsao PS
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MicroRNAs in abdominal aortic aneurysm. Curr Vasc Pharmacol. 2015;13(3):280-90
Adam M, Raaz U, Spin J, Tsao PS
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Systemic Upregulation of IL-10 (Interleukin-10) Using a Nonimmunogenic Vector Reduces Growth and Rate of Dissecting Abdominal Aortic Aneurysm. Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;38:1796–1805
Matti Adam, Nigel Kooreman, Ann Jagger, Markus U. Wagenhäuser, Dennis Mehrkens, Yongming Wang, Yosuke Kayama, Kensuke Toyama, Uwe Raaz, Isabel N. Schellinger, Lars Maegdefessel, Joshua M. Spin, Jaap F. Hamming, Paul H.A. Quax, Stephan Baldus, Joseph C. Wu
