Inhibition of proteasome-mediated glucocorticoid receptor degradation restores nitric oxide bioavailability in myocardial endothelial cells in vitro.

Abstract

BACKGROUND INFORMATION:

Glucocorticoids (GCs), including the synthetic GC derivate dexamethasone, are widely used as immunomodulators. One of the numerous side effects of dexamethasone therapy is hypertension arising from reduced release of the endothelium-derived vasodilator nitric oxide (NO).

RESULTS:

Herein, we described the role of dexamethasone and its glucocorticoid receptor (GR) in the regulation of NO synthesis in vitro using the mouse myocardial microvascular endothelial cell line, MyEND. GC treatment caused a firm decrease of extracellular NO levels, whereas the expression of endothelial NO synthase (eNOS) was not affected. However, GC application induced an impairment of tetrahydrobiopterin (BH4 ) concentrations as well as GTP cyclohydrolase-1 (GTPCH-1) expression, both essential factors for NO production upstream of eNOS. Moreover, dexamethasone stimulation resulted in a substantially decreased GR gene and protein expression in MyEND cells. Importantly, inhibition of proteasome-mediated proteolysis of the GR or overexpression of an ubiquitination-defective GR construct improved the bioavailability of BH4 and strengthened GTPCH-1 expression and eNOS activity.

CONCLUSIONS:

Summarising our results, we propose a new mechanism involved in the regulation of NO signalling by GCs in myocardial endothelial cells. We suggest that a sufficient GR protein expression plays a crucial role for the management of GC-induced harmful adverse effects, including deregulations of vasorelaxation arising from disturbed NO biosynthesis.

• Authors: Kinga G Blecharz, Malgorzata Burek, Johann Bauersachs, Thomas Thum, Dimitrios Tsikas, Julian Widder, Norbert Roewer, Carola Y Förster
• Journal: Biology of the cell (Biol Cell) Vol. 106 Issue 7 Pg. 219-35 (Jul 2014) ISSN: 1768-322X [Electronic] England
• PMID: 24749543 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.

Chemical References

• Glucocorticoids
• Receptors, Glucocorticoid
• Biopterins
• Dexamethasone
• Nitric Oxide Synthase Type III
• Proteasome Endopeptidase Complex
• GTP Cyclohydrolase
• sapropterin

Topics

• Animals
• Biopterins (analogs & derivatives, metabolism)
• Cell Line
• Coronary Vessels (metabolism)
• Dexamethasone (metabolism, pharmacology)
• Endothelial Cells (metabolism)
• GTP Cyclohydrolase (metabolism)
• Gene Expression Regulation (drug effects)
• Glucocorticoids (pharmacology)
• Mice
• Nitric Oxide Synthase Type III (biosynthesis)
• Proteasome Endopeptidase Complex (metabolism)
• Proteolysis
• Receptors, Glucocorticoid (genetics, metabolism)