Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency

Cynthia J. Meininger, Rebecca S. Marinos, Kazuyuki Hatakeyama, Raul Martinez-Zaguilan, Jose D. Rojas, Katherine A. Kelly, Guoyao Wu

Research output: Contribution to journalArticle

155 Scopus citations

Abstract

Endothelial cells (EC) from diabetic BioBreeding (BB) rats have an impaired ability to produce NO. This deficiency is not due to a defect in the constitutive isoform of NO synthase in EC (ecNOS) or alterations in intracellular calcium, calmodulin, NADPH or arginine levels. Instead, ecNOS cannot produce sufficient NO because of a deficiency in tetrahydrobiopterin (BH4), a cofactor necessary for enzyme activity. EC from diabetic rats exhibited only 12% of the BH4 levels found in EC from normal animals or diabetes-prone animals which did not develop disease. As a result, NO synthesis by EC of diabetic rats was only 18% of that for normal animals. Increasing BH4 levels with sepiapterin increased NO production, suggesting that BH4 deficiency is a metabolic basis for impaired endothelial NO synthesis in diabetic BB rats. This deficiency is due to decreased activity of GTP-cyclohydrolase I, the first and rate-limiting enzyme in the de novo biosynthesis of BH4. GTP-cyclohydrolase activity was low because of a decreased expression of the protein in the diabetic cells.

Original languageEnglish (US)
Pages (from-to)353-356
Number of pages4
JournalBiochemical Journal
Volume349
Issue number1
DOIs
StatePublished - Jul 1 2000
Externally publishedYes

Keywords

  • Diabetes
  • GTP-cyclohydrolase
  • Nitric oxide synthesis
  • Vascular disease

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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