Article

Characterization of transgenic Gfrp knock-in mice: Implications for tetrahydrobiopterin in modulation of normal tissue radiation responses.

UAMS, Division of Radiation Health, Little Rock, Arkansas, United States
Antioxidants & Redox Signaling (Impact Factor: 7.67). 03/2013; DOI: 10.1089/ars.2012.5025
Source: PubMed

ABSTRACT Aims: The free radical scavenger and nitric oxide synthase cofactor, tetrahydrobiopterin (BH4), plays a well-documented role in many disorders associated with oxidative stress, including normal tissue radiation responses. Radiation exposure is associated with decreased BH4 levels, while BH4 supplementation attenuates aspects of radiation toxicity. The endogenous synthesis of BH4 is catalyzed by the enzyme GTP Cyclohydrolase I (GTPCH1), which is regulated by the inhibitory GTP Cyclohydrolase I Feedback Regulatory Protein (GFRP). We here report and characterize a novel, Cre-Lox-driven, transgenic mouse model that overexpresses Gfrp. Results: Compared to control littermates, transgenic mice exhibited high transgene copy numbers, increased Gfrp mRNA and GFRP protein expression, enhanced GFRP-GTPCH1 interaction, reduced BH4 levels, as well as low glutathione (GSH) levels and differential mitochondrial bio-energetic profiles. After exposure to total body irradiation, transgenic mice showed decreased BH4/ BH2 ratios, increased vascular oxidative stress, and reduced white blood cell counts compared to controls. Innovation and conclusion: This novel Gfrp knock-in transgenic mouse model allows elucidation of the role of GFRP in the regulation of BH4 biosynthesis. The model is a valuable tool to study the involvement of BH4 in whole body and tissue-specific radiation responses and other conditions associated with oxidative stress.

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