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Endothelial cell–glucocorticoid receptor interactions and regulation of Wnt signaling
Han Zhou, … , William C. Sessa, Julie E. Goodwin
Han Zhou, … , William C. Sessa, Julie E. Goodwin
Published February 13, 2020
Citation Information: JCI Insight. 2020;5(3):e131384. https://doi.org/10.1172/jci.insight.131384.
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Research Article Inflammation Vascular biology

Endothelial cell–glucocorticoid receptor interactions and regulation of Wnt signaling

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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.

Authors

Han Zhou, Sameet Mehta, Swayam Prakash Srivastava, Kariona Grabinska, Xinbo Zhang, Chris Wong, Ahmad Hedayat, Paola Perrotta, Carlos Fernández-Hernando, William C. Sessa, Julie E. Goodwin

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Figure 3

Primer-specific qPCR for genes in the Wnt signaling pathway, which were identified in the top 1000 peaks of the glucocorticoid receptor (GR) ChIP-seq data set, was performed both in vitro and in vivo.

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Primer-specific qPCR for genes in the Wnt signaling pathway, which were ...
(A) Control siRNA– or GR siRNA–treated MLECs. Data represent 3 separate experiments. (B) Double knock-out (DKO) (n = 6) or control (Apoe–/–) mice (n = 3) fed with high-fat diet for 3 weeks. Whole aortas were dissected for RNA isolation and qPCR. Unpaired t test was used for each primer set. *P < 0.05. (C–E) Alignment of the input DNA with the Con DEX condition from the ChIP-seq data demonstrates massively enriched GR binding at the peak locations for Tcf7l2 (C), Arid1b (D), and Smad4 (E).

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