Vasopressin Type 1A Receptor Up-regulation by Cyclosporin A in Vascular Smooth Muscle Cells Is Mediated by Superoxide

Based on our previous results, we investigated whether cyclosporin A (CsA)-induced vasopressin type 1A receptor up-regulation was mediated by free radicals. We report that CsA analogues with different affinities for cyclophilin and calcineurin were able to up-regulate vasopressin type 1A receptor an...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-10, Vol.278 (43), p.41685-41690
Main Authors: Krauskopf, Alexandra, Lhote, Philippe, Mutter, Manfred, Dufour, Jean-François, Ruegg, Urs T., Buetler, Timo M.
Format: Article
Language:English
Subjects:
Animals
Aorta - cytology
Calcineurin - pharmacology
Catalase - metabolism
Cyclophilins - pharmacology
Cyclosporine - pharmacology
Free Radicals - metabolism
Male
Muscle, Smooth, Vascular - cytology
Rats
Rats, Wistar
Receptors, Vasopressin - biosynthesis
RNA, Messenger - biosynthesis
RNA, Messenger - drug effects
Superoxide Dismutase - metabolism
Superoxides - metabolism
Superoxides - pharmacology
Up-Regulation - drug effects
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Summary:Based on our previous results, we investigated whether cyclosporin A (CsA)-induced vasopressin type 1A receptor up-regulation was mediated by free radicals. We report that CsA analogues with different affinities for cyclophilin and calcineurin were able to up-regulate vasopressin type 1A receptor and to generate free radicals in smooth muscle cells independently of calcineurin. Further, we demonstrate that the antioxidant N-acetyl-l-cysteine blocked the increase in vasopressin type 1A receptor mRNA and protein levels induced by CsA and that low concentrations of prooxidants were able to directly increase vasopressin type 1A receptor mRNA and protein levels. In addition, short exposure to CsA or pro-oxidants was sufficient to significantly increase vasopressin type 1A receptor mRNA and protein levels. Using cell-permeable forms of superoxide dismutase and catalase, we finally show that superoxide mediates the CsA-induced effects on vasopressin type 1A receptor. These results provide strong evidence that CsA-induced superoxide generation is causally involved in vasopressin type 1A receptor expression and demonstrate for the first time that low physiological concentrations of radicals, most probably superoxide, are able to directly affect cellular signaling to increase vasopressin type 1A receptor expression in rat aortic smooth muscle cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M301181200