Atherosclerosis
Understanding how the endothelium regulates progression and stability, with the goal of achieving regression and resolution.
Cholesterol-lowering treatments for managing atherosclerosis do not completely reduce the inflammatory risk and associated risk of cardiovascular events in many individuals. This limitation is likely because the mechanisms promoting resolution of cardiovascular disease (CVD) are incompletely understood. Inflammation resolution requires a tight balance between pro-inflammatory cytokines (e.g. interleukins 1 and 6) and inhibitory signals (e.g. SOCS3) as well as proinflammatory leukotrienes or prostaglandins (such as LTB4, PGE2) and ω3-derived specialized pro-resolving mediators (SPMs), like resolvins. Atherosclerosis is associated with increased IL-6 signaling and a reduced SPM:LT or PG mediator ratio, and a “pro-atherogenic” (inflammatory) endothelial phenotype. However, major gaps exist in our understanding of (a) the mechanisms regulating impaired resolution in cholesterol-lowering settings, and (b) how SOCS3 and SPMs promote resolution. Our objective is to investigate mechanisms of inflammation resolution within endothelial cells that limit the progression of atherosclerotic plaques and promote repair in the context of cholesterol-lowering regimens. We found new regulatory signaling loops between pro-inflammatory cytokines and pro-resolving signals within endothelial cells that reduce (IL-6) or increase (SPMs or SOCS3) atherosclerotic plaque cap thickness.
Our work aims to identify endothelial-specific targets that can shift the balance from plaque progression toward regression and resolution, ultimately reducing the risk of heart attack and stroke.