Proteasome-dependent degradation of guanosine 5'-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus.

Proteasome-dependent degradation of guanosine 5'-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus. Research Abstract Details 

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Proteasome-dependent degradation of guanosine 5'-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus. Abstract Text:

Jian Xu,Yong Wu,Ping Song,Miao Zhang,Shuangxi Wang,Ming-Hui Zou,

BACKGROUND: Tetrahydrobiopterin (BH4) deficiency is reported to uncouple the enzymatic activity of endothelial nitric oxide synthase in diabetes mellitus. The mechanism by which diabetes actually leads to BH4 deficiency remains elusive. Here, we demonstrate that diabetes reduced BH4 by increasing 26S proteasome-dependent degradation of guanosine 5'-triphosphate cyclohydrolase I (GTPCH), a rate-limiting enzyme in the synthesis of BH4, in parallel with increased formation of both superoxide and peroxynitrite (ONOO-). METHODS AND RESULTS: Exposure of human umbilical vein endothelial cells to high glucose concentrations (30 mmol/L D-glucose) but not to high osmotic conditions (25 mmol/L L-glucose plus 5 mmol/L D-glucose) significantly lowered the levels of both GTPCH protein and BH4. In addition, high glucose increased both the 26S proteasome activity and the ubiquitination of GTPCH. Inhibition of the 26S proteasome with either MG132 or PR-11 prevented the high glucose-triggered reduction of GTPCH and BH4. Exposure of human umbilical vein endothelial cells to exogenous ONOO- increased proteasome activity and 3-nitrotyrosine in 26S proteasome. Furthermore, adenoviral overexpression of superoxide dismutase and inhibition of endothelial nitric oxide synthase with N(G)-nitro-L-arginine methyl ester significantly attenuated the high glucose-induced activation of 26S proteasome and the reduction of GTPCH. Finally, administration of MG132 or a superoxide dismutase mimetic, tempol, reversed the diabetes mellitus-induced reduction of GTPCH and BH4 and endothelial dysfunction in streptozotocin-induced diabetes mellitus. CONCLUSIONS: We conclude that diabetes mellitus triggers BH4 deficiency by increasing proteasome-dependent degradation of GTPCH.

Proteasome-dependent degradation of guanosine 5'-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus. Publishing Authors By Initials

J Xu,Y Wu,P Song,M Zhang,S Wang,MH Zou,

For similar cardiovascular system: blood vessels: veins: portal system: umbilical veins research abstracts see: cardiovascular system: blood vessels: veins: portal system: umbilical veins research

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Proteasome-dependent degradation of guanosine 5'-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Circulation

VOLUME: 116

Page Numbers: 944-53

Journal Abbreviation: Circulation

ISSN: 1524-4539

DAY: 6

MONTH: 08

YEAR: 2007

Proteasome-dependent degradation of guanosine 5'-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 147763

Proteasome-dependent degradation of guanosine 5'-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus. Keywords Mesh Terms:

KEYWORDS: Umbilical Veins

MESH TERMS: cytology

Chemical & Substance for Abstract: Proteasome-dependent degradation of guanosine 5'-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus. Information

Substance Name: GTP Cyclohydrolase

Registry Number: EC 3.5.4.16

Grant and Affiliation Information for Proteasome-dependent degradation of guanosine 5'-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus.

AFFILIATION: Division of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: HL080499

ACRONYM: HL

MEDLINETA: Circulation

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