Down-Regulation of the Expression of Endothelial NO Synthase Is Likely to Contribute to Glucocorticoid-Mediated Hypertension

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 23; pp. 13357 - 13362
• Main Authors: Wallerath, Thomas, Witte, Klaus, Schäfer, Stephan C., Schwarz, Petra M., Prellwitz, Winfried, Wohlfart, Paulus, Kleinert, Hartmut, Lehr, Hans-Anton, Lemmer, Björn, Förstermann, Ulrich
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 09.11.1999; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Animals; Aorta - drug effects; Aorta - metabolism; Base Sequence; Biological Sciences; Blood pressure; Cells, Cultured; Dexamethasone - pharmacology; DNA Primers; Down regulation; Drug therapy; Endothelial cells; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Enzymes; GATA protein; GATA transcription factors; Genes; Glucocorticoids; Human umbilical vein endothelial cells; Hypertension; Hypertension - chemically induced; Hypertension - metabolism; Male; Messenger RNA; mifepristone; Nitrates - blood; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type III; Nitrites - blood; Oligonucleotides; Promoter Regions, Genetic; Rats; Rats, Inbred WKY; RNA, Messenger - genetics; RNA, Messenger - metabolism; S-nitroso-N-acetyl-D,L-penicillamine; Transcription Factors - metabolism; Ungulates; Vasodilation - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.23.13357

Hypertension is a side effect of systemically administered glucocorticoids, but the underlying molecular mechanism remains poorly understood. Ingestion of dexamethasone by rats telemetrically instrumented increased blood pressure progressively over 7 days. Plasma concentrations of Na+ and K+ and urinary Na+ and K+ excretion remained constant, excluding a mineralocorticoid-mediated mechanism. Plasma NO2-/NO3- (the oxidation products of NO) decreased to 40%, and the expression of endothelial NO synthase (NOS III) was found down-regulated in the aorta and several other tissues of glucocorticoid-treated rats. The vasodilator response of resistance arterioles was tested by intravital microscopy in the mouse dorsal skinfold chamber model. Dexamethasone treatment significantly attenuated the relaxation to the endothelium-dependent vasodilator acetylcholine, but not to the endothelium-independent vasodilator S-nitroso-N-acetyl-D,L-penicillamine. Incubation of human umbilical vein endothelial cells, EA.hy 926 cells, or bovine aortic endothelial cells with several glucocorticoids reduced NOS III mRNA and protein expression to 60-70% of control, an effect that was prevented by the glucocorticoid receptor antagonist mifepristone. Glucocorticoids decreased NOS III mRNA stability and reduced the activity of the human NOS III promoter (3.5 kilobases) to ≈ 70% by decreasing the binding activity of the essential transcription factor GATA. The expressional down-regulation of endothelial NOS III may contribute to the hypertension caused by glucocorticoids.