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Endothelial glucocorticoid receptor is required for protection against sepsis

Goodwin, Julie E., Feng, Yan, Velazquez, Heino, Sessa, William C.
Proceedings of the National Academy of Sciences of the United States of America 2013 v.110 no.1 pp. 306-311
apoptosis, endothelial nitric oxide synthase, genes, glucocorticoid receptors, hemodynamics, humans, inducible nitric oxide synthase, interleukin-6, macrophages, messenger RNA, mice, mortality, nitric oxide, phenotype, quantitative polymerase chain reaction, sepsis (infection), small interfering RNA, transcription factor NF-kappa B, tumor necrosis factor-alpha
The glucocorticoid receptor (GR) is ubiquitously expressed on nearly all cell types, but tissue-specific deletion of this receptor can produce dramatic whole organism phenotypes. In this study we investigated the role of the endothelial GR in sepsis in vivo and in vitro. Mice with an endothelial-specific GR deletion and controls were treated with 12.5 mg/kg LPS and phenotyped. Mice lacking GR showed significantly increased mortality, more hemodynamic instability, higher nitric oxide levels, and higher levels of the inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) compared with controls. There were no differences in rates of apoptosis or macrophage recruitment between the two groups. Both endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) expression were increased after LPS challenge in mice with endothelial GR deficiency, and aminoguanidine, a specific iNOS inhibitor in mice was able to rescue hemodynamic collapse in these animals. In vitro, human umbilical vein cells (HUVECs) subjected to GR knockdown by siRNA showed increased expression of eNOS at baseline that persisted after treatment with LPS. Both eNOS and iNOS mRNA was increased by qPCR. In HUVECs lacking GR, NF-κB levels and NF-κB–dependent genes tissue factor and IL-6 were increased compared with controls. Thus, endothelial GR is a critical regulator of NF-κB activation and nitric oxide synthesis in sepsis.