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A Macrophage Rac1-IL1B Signaling Axis Directs Atherosclerotic Calcification


Atherosclerotic plaque calcification is associated increased risk of cardiovascular events. Inflammation plays a key role in the development of atherosclerosis and is thought to potentially participate in vascular calcification. 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitors or statins, which are used to reduce risk of cardiovascular events, appear to alter plaque calcification. However, the signaling mechanisms that promote this process and how statins alter these mechanisms are minimally understood. Prior investigation of these mechanisms defined a macrophage Rac (Ras-related C3 botulinum toxin substrate)-IL-1β (interleukin-1 beta) signaling axis as important in promoting atherosclerotic calcification in Rac2 deficient mice, which exhibit elevated calcification. This project sought to evaluate the role of Rac-IL-1β signaling in endogenous atherosclerotic calcification and to investigate the role of statin therapy in this pathway. Both endogenous macrophage Rac1 expression and Rac1-dependent IL-1β expression are demonstrated to contribute to the development of atherosclerotic calcification. Statins are shown to enhance calcification by disrupting the complex between Rac1 and its inhibitor RhoGDI (Rho GDP-dissociation inhibitor), leading to increased Rac1 activity (GTP bound) in primary monocytes/macrophages. Rac1 regulation of IL-1β expression appears to be dependent upon NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity in both endogenous and statin-treated macrophage signaling under inflammasome stimulation. These findings demonstrate that macrophage endogenous Rac1-IL-1β signaling is important for atherosclerotic calcification and that statin-enhanced calcification is facilitated through this same signaling axis by disrupting the inhibition of Rac1 activity.
Thesis (Ph. D.)--Brown University, 2020

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Berus, Joshua, "A Macrophage Rac1-IL1B Signaling Axis Directs Atherosclerotic Calcification" (2020). Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations. Brown Digital Repository. Brown University Library.