Coronary artery disease from calcific atherosclerosis is the leading cause of morbidity and mortality in the world. The calcium composition of atherosclerotic plaque has predictive value in terms of cardiovascular events. Inflammation is likely a key mediator of vascular calcification, but immune signaling mechanisms that promote this process are minimally understood. Recently, the inflammatory cytokine, IL-1?, was identified to be increased in calcifying atherosclerotic aortas from ApoE-/- background mice fed a high fat diet. Moreover, plaque and serum from mice with progressive calcification demonstrated increased expression of IL-1?. Treatment with the IL-1 receptor antagonist inhibited atherosclerotic calcification. IL-1? expression was a key driver of vascular smooth muscle cell calcium deposition by its ability to promote expression of the osteogenic transcription factors, RUNX2, SOX9, OSX and MSX2. Bone marrow transplantation confirmed that progressive calcification of plaque is attributable to the hematopoietic compartment. Several key questions remain: 1) are macrophages the key cellular source of plaque IL-1? during atherosclerotic calcification; 2) do vascular smooth muscle cells take on an inflammatory phenotype to promote plaque IL-1? expression; 3) what are the effects of IL-1 receptor signaling on both plaque macrophages and vascular smooth muscle cells; 4) how does IL-1 receptor signaling lead to an osteogenic gene program; and 5) can IL-1? serve as a biomarker of progressive calcification in patients with coronary artery disease. Preliminary data demonstrated that macrophages appear associated with expression of IL-1? in plaque, and consequently, IL-1? signaling through its receptor may play an autocrine positive feedback role in promoting further IL-1? expression by macrophages. Vascular smooth muscle cells, in contrast, appear to play a responsive role to IL-1? signaling by activating an osteogenic gene program. However, global deletion of the IL-1 receptor demonstrated conflicting data about whether nonspecific inhibition of IL-1? signaling can protect against plaque vulnerability, indicating further study to delineate cell-specific contributions in this pathway is required. The hypothesis is that macrophage expression of IL-1? in atherosclerotic plaque and consequent vascular cell IL-1 receptor signaling lead to inflammatory atherosclerotic calcification resulting in increased risk of plaque rupture.
Aim 1 will define macrophage IL-1? expression as the critical to inflammatory atherosclerotic calcification.
Aim 2 will determine the respective roles of macrophage and smooth muscle cell IL-1 receptor signaling in inflammatory atherosclerotic calcification and osteogenic transcription factor expression.
Aim 3 will validate serum IL-1? as a critical biomarker of progressive coronary artery calcification in patients. Confirming that a macrophage IL-1? signaling axis is a central mechanism in inflammatory atherosclerotic calcification in preclinical and translational studies paves the way for developing a novel therapeutic strategy aimed at treating risk in coronary artery disease, as anti-IL- 1? therapies have been developed and are actively under investigation.
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