Article (Scientific journals)
AT2 receptor activation regulates myocardial eNOS expression via the calcineurin-NF-AT pathway.
Ritter, Oliver; Schuh, Kai; Brede, Marc et al.
2003In FASEB Journal, 17 (2), p. 283-5
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Keywords :
Angiotensin II/pharmacology; Animals; Animals, Newborn; Base Sequence; Binding Sites/genetics; Calcineurin/metabolism; DNA-Binding Proteins/metabolism; Humans; Luciferases/genetics/metabolism; Mice; Mice, Knockout; Myocardium/cytology/enzymology; NFATC Transcription Factors; Nitric Oxide Synthase/drug effects/genetics/metabolism; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nuclear Proteins; Promoter Regions, Genetic/genetics; Protein Binding; Rats; Receptor, Angiotensin, Type 2; Receptors, Angiotensin/genetics/metabolism; Recombinant Fusion Proteins/drug effects/genetics/metabolism; Signal Transduction; Transcription Factors/metabolism; Transfection
Abstract :
[en] The role of AT2-receptors has recently been subject of considerable debate. We investigated the influence of AT2-stimulation/inhibition on myocardial endothelial NO-synthase (eNOS, NOS-III) promoter activity and eNOS protein expression. Stimulation of rat cardiomyocytes with angiotensin II (AngII) increased eNOS protein expression 3.3-fold. This was blocked by Cyclosporin A (CsA). Inhibition of the AT1-receptor did not reduce AngII-mediated eNOS protein expression, whereas AT2 stimulation increased it 2.4-fold and AT2 inhibition suppressed it. The modulatory effects of the AT2-receptor on eNOS expression was confirmed in mice with a genetic deletion of the AT2-receptor (AT2-KO). In gel shift assays two putative NF-AT sites in a 1.6 kb eNOS promoter fragment showed NF-AT binding and a supershift by NF-AT2(-c1)-specific antibodies. Stimulation of transfected cells with AngII or specific AT2-receptor agonists resulted in a significant increase in eNOS promoter activity, which was blocked by CsA, MCIP1, and mutation of an upstream NF-AT site. CONCLUSION: 1) AngII-stimulation of the myocardium, both in vivo and in vitro, is accompanied by increased expression of eNOS. 2) This effect is mediated by the calcineurin pathway and is induced by the AT2-receptor. 3) These results define a calcineurin/NF-AT/eNOS pathway as downstream effector of AT2-receptor activation in the myocardium.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
Ritter, Oliver
Schuh, Kai
Brede, Marc
Rothlein, Nicola
Burkard, Natalie
Hein, Lutz
Neyses, Ludwig ;  University of Luxembourg > Research Office
Language :
English
Title :
AT2 receptor activation regulates myocardial eNOS expression via the calcineurin-NF-AT pathway.
Publication date :
2003
Journal title :
FASEB Journal
ISSN :
1530-6860
Publisher :
Federation of American Societies for Experimental Biology, United States - Maryland
Volume :
17
Issue :
2
Pages :
283-5
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 16 October 2014

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