Glucocorticoids Downregulate Cyclooxygenase-1 Gene Expression and Prostacyclin Synthesis in Fetal Pulmonary Artery Endothelium via Activation of Endothelial Glucocorticoid Receptors ♦ 116

Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated.

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Abstract 5953: Flow Pulsation Affect Distal Pulmonary Artery Endothelial Cell mRNA Expression

Circulation ◽

10.1161/circ.118.suppl_18.s_1037-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Min Li ◽

Kurt Stenmark ◽

Robin Shandas ◽

Wei Tan

Keyword(s):

Gene Expression ◽

Pulmonary Artery ◽

Pulsatile Flow ◽

Static Condition ◽

Flow Chamber ◽

Physical Characteristics ◽

List Type ◽

Flow Pulsation ◽

Individual Gene ◽

Speed Flow

Background: Due to the development of pulmonary arterial hypertension (PAH), distal pulmonary artery endothelial cells (dPAEC) are exposed to wall shear stress (SS) that is different in physical characteristics compared to normal condition. The effect of individual components of SS on PAEC biology has not been thoroughly examined. Thus the current study was designed to examine how dPAEC respond to different component of SS in regarding to gene expression including adhesion molecules: ICAM, VCAM, E-selectin; chemokine: MCP-1 and growth factors:VEGF, Flt-1. Methods: Bovine dPAEC were cultured and placed on fibronectin-coated slides till confluent. Cells were then exposed to SS with different frequency (1Hz, 2Hz), pulsation (low, medium and high with an average SS of 14 dynes/cm 2 ) and time (1hr or 6hrs). The flow studies were carried out using a flow chamber connected to a variable speed flow pump. All data was represented as fold change relative to static condition. Results: As shown in table below, The effect of flow frequency on gene expression depends on individual gene. There was no difference of ICAM expression between 1Hz and 2Hz. Frequency of 2Hz significantly increased VCAM and MCP-1 expression compared to frequency of 1Hz. Compared to static condition, steady flow increased all gene expression. One hour pulsatile flow further increased ICAM, VCAM, E-selectin and MCP-1 but not VEGF or Flt-1 expression as pulsation increased. 3) Prolonged pulsatile flow further increased all gene expression. Conclusion: Physical characteristics of flow, especially flow pulsation stimulate dPAEC gene expression which can contribute to the development of PAH.

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The Regulation of Prostaglandin E2 Synthesis by Interleukin-1β and Ceramide in Human Fibroblasts: Effects on Cyclooxygenase-1, Cyclooxygenase-2, and Phospholipase A2 Gene Expression

Frontiers in Bioactive Lipids ◽

10.1007/978-1-4615-5875-0_16 ◽

1996 ◽

pp. 111-117

Author(s):

Leslie R. Ballou ◽

Kanyawim Kirtikara ◽

Stanley J. F. Laulederkind

Keyword(s):

Gene Expression ◽

Prostaglandin E2 ◽

Phospholipase A2 ◽

Human Fibroblasts ◽

Cyclooxygenase 2 ◽

Interleukin 1Β ◽

Cyclooxygenase 1

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Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors.

Molecular and Cellular Biology ◽

10.1128/mcb.15.2.943 ◽

1995 ◽

Vol 15 (2) ◽

pp. 943-953 ◽

Cited By ~ 570

Author(s):

R I Scheinman ◽

A Gualberto ◽

C M Jewell ◽

J A Cidlowski ◽

A S Baldwin

Keyword(s):

Gene Expression ◽

Hela Cells ◽

Transcriptional Activation ◽

Glucocorticoid Receptors ◽

Interleukin 1 ◽

Direct Interaction ◽

Significant Loss ◽

Nf Kappa B ◽

Necrosis Factor Alpha ◽

Important Regulator

Glucocorticoids are potent immunosuppressants which work in part by inhibiting cytokine gene transcription. We show here that NF-kappa B, an important regulator of numerous cytokine genes, is functionally inhibited by the synthetic glucocorticoid dexamethasone (DEX). In transfection experiments, DEX treatment in the presence of cotransfected glucocorticoid receptor (GR) inhibits NF-kappa B p65-mediated gene expression and p65 inhibits GR activation of a glucocorticoid response element. Evidence is presented for a direct interaction between GR and the NF-kappa B subunits p65 and p50. In addition, we demonstrate that the ability of p65, p50, and c-rel subunits to bind DNA is inhibited by DEX and GR. In HeLa cells, DEX activation of endogenous GR is sufficient to block tumor necrosis factor alpha or interleukin 1 activation of NF-kappa B at the levels of both DNA binding and transcriptional activation. DEX treatment of HeLa cells also results in a significant loss of nuclear p65 and a slight increase in cytoplasmic p65. These data reveal a second mechanism by which NF-kappa B activity may be regulated by DEX. We also report that RU486 treatment of wild-type GR and DEX treatment of a transactivation mutant of GR each can significantly inhibit p65 activity. In addition, we found that the zinc finger domain of GR is necessary for the inhibition of p65. This domain is also required for GR repression of AP-1. Surprisingly, while both AP-1 and NF-kappa B can be inhibited by activated GR, synergistic NF-kappa B/AP-1 activity is largely unaffected. These data suggest that NF-kappa B, AP-1, and GR interact in a complex regulatory network to modulate gene expression and that cross-coupling of NF-kappa B and GR plays an important role in glucocorticoid-mediated repression of cytokine transcription.

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