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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 4

In vitro regulation of canonical Wnt signaling by the glucocorticoid receptor (GR).

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In vitro regulation of canonical Wnt signaling by the glucocorticoid rec...
Mouse lung endothelial cells (MLECs) were serum starved in 0.5% FBS for 4 hours and then treated with 10% Wnt3a conditioned media for 6 hours. Dexamethasone (DEX) 100 nM was added for 1 hour at the completion of the media incubation period. (A and B) qPCR for Sox17 (A) and Axin2 (B) was performed. (C) Control siRNA or GR siRNA MLECs were treated with Wnt3a 200 ng/mL for 4 hours in the presence or absence of DEX 100 nM for 1 hour, and qPCR for Sox17 was performed. (D) MLECs were stably transfected with a TCF/LEF luciferase construct and subjected to either control siRNA or GR siRNA treatment, with and without Wnt3a 200 mg/mL for 4 hours. (E) MLECs were treated with either control siRNA or GR siRNA, and lysates were subjected to Western blot for GR and β-catenin expression. (F) Quantification of GR and β-catenin expression by densitometry. Data represent 3 independent experiments. One-way ANOVA with Tukey’s post hoc test was used to analyze data in A, B, and D. Student’s t test was used to analyze data in C and F. *P < 0.05; **P < 0.01.

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