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 language | English (US) |
|---|---|
| Pages (from-to) | 353-356 |
| Number of pages | 4 |
| Journal | Biochemical Journal |
| Volume | 349 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 1 2000 |
| Externally published | Yes |
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Keywords
- Diabetes
- GTP-cyclohydrolase
- Nitric oxide synthesis
- Vascular disease
ASJC Scopus subject areas
- Biochemistry
Cite this
Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency. / Meininger, Cynthia J.; Marinos, Rebecca S.; Hatakeyama, Kazuyuki; Martinez-Zaguilan, Raul; Rojas, Jose; Kelly, Katherine A.; Wu, Guoyao.
In: Biochemical Journal, Vol. 349, No. 1, 01.07.2000, p. 353-356.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency
AU - Meininger, Cynthia J.
AU - Marinos, Rebecca S.
AU - Hatakeyama, Kazuyuki
AU - Martinez-Zaguilan, Raul
AU - Rojas, Jose
AU - Kelly, Katherine A.
AU - Wu, Guoyao
PY - 2000/7/1
Y1 - 2000/7/1
N2 - 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.
AB - 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.
KW - Diabetes
KW - GTP-cyclohydrolase
KW - Nitric oxide synthesis
KW - Vascular disease
UR - http://www.scopus.com/inward/record.url?scp=0034235409&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034235409&partnerID=8YFLogxK
U2 - 10.1042/0264-6021:3490353
DO - 10.1042/0264-6021:3490353
M3 - Article
C2 - 10861247
AN - SCOPUS:0034235409
VL - 349
SP - 353
EP - 356
JO - Biochemical Journal
JF - Biochemical Journal
SN - 0264-6021
IS - 1
ER -