Abstract
Vascular inflammation is present in many cardiovascular diseases, and exogenous glucocorticoids have traditionally been used as a therapy to suppress inflammation. However, recent data have shown that endogenous glucocorticoids, acting through the endothelial glucocorticoid receptor, act as negative regulators of inflammation. Here, we performed ChIP for the glucocorticoid receptor, followed by next-generation sequencing in mouse endothelial cells to investigate how the endothelial glucocorticoid receptor regulates vascular inflammation. We identified a role of the Wnt signaling pathway in this setting and show that loss of the endothelial glucocorticoid receptor results in upregulation of Wnt signaling both in vitro and in vivo using our validated mouse model. Furthermore, we demonstrate glucocorticoid receptor regulation of a key gene in the Wnt pathway, Frzb, via a glucocorticoid response element gleaned from our genomic data. These results suggest a role for endothelial Wnt signaling modulation in states of vascular inflammation.
Highlights
Inflammation is a complex cascade of adaptive cellular responses to injurious stimuli, which occurs in many cardiovascular diseases [1]
The duration of DEX treatment was replicated from a previous ChIP study [10], and knockdown of glucocorticoid receptor (GR) using this siRNA is greater than 80% [6]
Control siRNA samples were 2.63% enriched in GR elements, which is within the expected range of 1%–7% for ChIP experiments [11]; after treatment with GR siRNA, enrichment was reduced to 0.02%, confirming excellent knockdown via siRNA and high specificity of the GR ChIP antibody
Summary
Inflammation is a complex cascade of adaptive cellular responses to injurious stimuli, which occurs in many cardiovascular diseases [1]. Administration of exogenous GCs as antiinflammatory agents provides systemic ligand to all cells expressing the glucocorticoid receptor (GR). Under these conditions, the particular role of a tissue-specific GR in resolving inflammation cannot be examined nor can the role of the endogenous ligand, cortisol. Endothelial GR represses a number of genes critical for the regulation of Wnt signaling pathway This pathway is independent from that of NF-κB, a classic target for GR, [8, 9] and highlights the permissive effects of cortisol in physiologically relevant states
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