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

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.

altmetric score

  • 6

author list (cited authors)

  • MEININGER, C. J., MARINOS, R. S., HATAKEYAMA, K., MARTINEZ-ZAGUILAN, R., ROJAS, J. D., KELLY, K. A., & WU, G.

citation count

  • 121

publication date

  • June 2000
  • January 1, 2000 11:11 AM