Epigenome-Guided Analysis of the Transcriptome of Plaque Macrophages during Atherosclerosis Regression Reveals Activation of the Wnt Signaling Pathway

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Atherosclerosis, a progressive accumulation of lipid-rich plaque within arteries, is an inflammatory disease in which the response of macrophages (a key cell type of the innate immune system) to plasma lipoproteins plays a central role. In humans, the goal of significantly reducing already-established plaque through drug treatments, including statins, remains elusive. In mice, atherosclerosis can be reversed by experimental manipulations that lower circulating lipid levels. A common feature of many regression models is that macrophages transition to a less inflammatory state and emigrate from the plaque. While the molecular regulators that control these responses are largely unknown, we hypothesized that by integrating global measurements of macrophage gene expression in regressing plaques with measurements of the macrophage chromatin landscape, we could identify key molecules that control macrophage responses to the lowering of circulating lipid levels. Our systems biology analysis of plaque macrophages yielded a network in which the Wnt signaling pathway emerged as a candidate upstream regulator. Wnt signaling is known to affect both inflammation and the ability of macrophages to migrate from one location to another, and our targeted validation studies provide evidence that Wnt signaling is increased in plaque macrophages during regression. Our findings both demonstrate the power of a systems approach to uncover candidate regulators of regression and to identify a potential new therapeutic target.

Vyšlo v časopise: Epigenome-Guided Analysis of the Transcriptome of Plaque Macrophages during Atherosclerosis Regression Reveals Activation of the Wnt Signaling Pathway. PLoS Genet 10(12): e32767. doi:10.1371/journal.pgen.1004828
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004828

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