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Diminished production of nitric oxide synthase cofactor tetrahydrobiopterin by rosiglitazone in adipocytes

Linscheid, Philippe and Keller, Ulrich and Blau, Nenad and Schaer, Dominik J. and Muller, Beat. (2003) Diminished production of nitric oxide synthase cofactor tetrahydrobiopterin by rosiglitazone in adipocytes. Biochemical pharmacology, Vol. 65, issue. 4. pp. 593-598.

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Official URL: http://edoc.unibas.ch/dok/A6419940

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Abstract

Increased nitric oxide (NO) synthesis has been proposed to participate in the generation of insulin resistance in adipose and muscle tissues. Therefore, we examined the potential rate-limiting role of tetrahydrobiopterin (BH4) in cytokine-induced NO synthesis, and the effect of peroxisome proliferator activated receptor-gamma (PPARgamma) activation using the insulin-sensitizer rosiglitazone on cytokine-induced BH4 synthesis in 3T3-L1 adipocytes. Our data indicate that modulated availability of the mandatory nitric oxide synthase (NOS) cofactor BH4 affected cytokine-induced NO generation. Semiquantitative linear range reverse transcription polymerase chain reaction (RT-PCR) analysis demonstrated that rosiglitazone not only reduced inducible nitric oxide synthase (iNOS) mRNA transcription, but also guanosine triphosphate cyclohydrolase (GTPCH), the rate-limiting and controlling step of BH4 synthesis. Accordingly, intracellular BH4 concentration was reduced by 45% following rosiglitazone treatment. Furthermore, we observed a transient inhibitory effect of natural PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PJ2) on cytokine-mediated iNOS and GTPCH induction. Thus, the inhibition of cytokine-induced NO synthesis by rosiglitazone is at least in part attributable to reduced availability of BH4, the synthesis of which might represent a potential new target in the treatment of type 2 diabetes and insulin resistance.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Ehemalige Einheiten Medizinische Fächer (Klinik) > Klinische Endokrinologie (Keller)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Ehemalige Einheiten Medizinische Fächer (Klinik) > Klinische Endokrinologie (Keller)
03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Metabolism (Keller/Müller)
UniBasel Contributors:Keller, Ulrich O. and Müller, Beat
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Elsevier
ISSN:0006-2952
e-ISSN:1873-2968
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:23 Nov 2017 10:45
Deposited On:02 Oct 2015 10:00

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