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

2000 ◽  
Vol 349 (1) ◽  
pp. 353-356 ◽  
Author(s):  
Cynthia J. MEININGER ◽  
Rebecca S. MARINOS ◽  
Kazuyuki HATAKEYAMA ◽  
Raul MARTINEZ-ZAGUILAN ◽  
Jose D. ROJAS ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
De Novo ◽  
Diabetic Rats ◽  
Bb Rat ◽  
No Production ◽  
Gtp Cyclohydrolase I ◽  
Gtp Cyclohydrolase ◽  
Bb Rats ◽  
Metabolic Basis ◽  
Rate Limiting

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.

Induction of tetrahydrobiopterin synthesis in rat cardiac myocytes: impact on cytokine-induced NO generation

1997 ◽  
Vol 273 (2) ◽  
pp. H665-H672 ◽  
Author(s):  
K. Kasai ◽  
Y. Hattori ◽  
N. Banba ◽  
S. Hattori ◽  
S. Motohashi ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
De Novo ◽  
Limit Of Detection ◽  
Interleukin 1 ◽  
Significant Rise ◽  
No Production ◽  
Gtp Cyclohydrolase I ◽  
Gtp Cyclohydrolase ◽  
Ifn Gamma ◽  
Rat Cardiac Myocytes

Because tetra-hydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) formation, we investigated whether BH4 synthesis is required for cytokine-induced NO production in cultured rat cardiac myocytes. The total biopterin content of untreated cardiac myocytes was below our limit of detection. However, treatment with interleukin-1 alpha (IL-1 alpha) + interferon-gamma (IFN-gamma) caused a significant rise in biopterin levels and induced NO synthesis. 2,4-Diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of GTP cyclohydrolase I (the rate-limiting enzyme for de novo BH4 synthesis), completely abolished the elevation in biopterin levels induced by IL-1 alpha + IFN-gamma. DAHP also caused a concentration-dependent inhibition of (IL-1 alpha + IFN-gamma)-induced NO synthesis. Similarly, N-acetylserotonin, an inhibitor of the BH4 synthetic enzyme sepiapterin reductase, blocked increases in biopterin levels as well as NO synthesis induced by IL-1 alpha + IFN-gamma. Sepiapterin, substrate for BH4 synthesis via the pterin salvage pathway, prevented this inhibition by DAHP or N-acetylserotonin, and this effect was blocked by methotrexate. Sepiapterin and, to a lesser extent, BH4 dose dependently enhanced (IL-1 alpha + IFN-gamma)-induced NO synthesis, suggesting that the concentration of BH4 limits the rate of NO production. Inducible NO synthase mRNA and GTP cyclohydrolase I mRNA were induced by IL-1 alpha + IFN-gamma in parallel. We thus demonstrate that BH4 synthesis is an absolute requirement for induction of NO synthesis by cytokines in cardiac myocytes.

Statin Increases GTP Cyclohydrolase I mRNA and 5,6,7,8-Tetrahydrobiopterin in Vascular Endothelial Cells

Pteridines ◽  
2006 ◽  
Vol 17 (3) ◽  
pp. 65-68
Author(s):  
Yoshiyuki Hattori ◽  
Nobuo Nakanishi
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
No Production ◽  
Mrna Levels ◽  
Gtp Cyclohydrolase I ◽  
Gtp Cyclohydrolase ◽  
Reductase Inhibitors ◽  
Enos Mrna ◽  
The Stability

Abstract We investigated the effects of HMG-CoA reductase inhibitors, so-called statins, on 5,6,7,8-tctrahydrobioptcrin (BH4) metabolism in human umbilical vein endothelial cells (HUVEC). The mRNA of GTP cyclohydrolase I (GTPCH), as well as cNOS, was upregulated in HUVEC treated with cerivastatin. This increase was time- and dose-dependent. Fluvastatin was also observed to enhance GTPCH and eNOS mRNA levels. In parallel with this observation, cerivastatin increased intracellular BH4. Cerivastatin increased the stability of eNOS mRNA. However, it did not alter the stability of GTPCH mRNA but increased GTPCH gene transcription as shown by nuclear run-on assays. Preteatment of HUVEC with the selective GTPCH inhibitor, 2,4-diamino-6-hydroxypyrimidine, caused a decrease in intracellular BH4 and decreased citrulline formation following stimulation with ionomycin. Furthermore, the potentiating effect of cerivasatin was decreased by limiting the cellular availability of BH4. In addition to augmenting eNOS expression, statins potentiate GTPCH gene expression and BH4 synthesis, thereby increasing NO production and preventing relative shortages of BH4

Stimulation of Tetrahydrobiopterin Synthesis by 17β-Estradiol in Brain Microvascular Endothelial Cells

Pteridines ◽  
2000 ◽  
Vol 11 (4) ◽  
pp. 129-132
Author(s):  
Kazuhiro Shiota ◽  
Masakazu Ishii ◽  
Toshinori Yamamoto ◽  
Shunichi Shimizu ◽  
Yuji Kiuchi
Keyword(s):  
Endothelial Cells ◽  
De Novo ◽  
Vascular Endothelial Cells ◽  
Mrna Level ◽  
Microvascular Endothelial Cells ◽  
No Production ◽  
Brain Microvascular Endothelial Cells ◽  
Protective Effects ◽  
17Β Estradiol ◽  
Microvascular Endothelial

Abstract The purpose of this study was to examine whether 17β-estradiol stimulates the synthesis of tetrahydrobiopterin : BH4), which is one of the cofactors of nitric oxide (NO) synthase, in mouse brain microvascular endothelial cells. Addition of 17()-estradiol to endothelial cells time- and concentration-dependently increased intracellular BH4 level. 17β-Estradiol also stimulated the mRNA level of GTP-cyclohydrolase I (GTPCH), which is a rate-limiting enzyme of the de novo BH4 synthetic pathway. In addition, the 17β-estradiol-induced expression of GTPCH mRNA was strongly attenuated by treatment with an inhibitor of 17β-estradiol receptor 4-hydroxy-tamoxlfen. These results suggest that 17β-estradiol stimulates BH4 synthesis through the induction of GTPCH by tamoxifensensitive receptor in vascular endothelial cells. The 17β-estradiol-induced increase in BH4 level might be implicated in not only NO production, but also protective effects of 17β-estradiol against ischemic brain damage and atherosclerosis, since BH4 is an intracellular antioxidant.

15-Deoxy-Δ12,14-prostaglandin J2 and peroxisome proliferator-activated receptor γ (PPARγ) levels in term placental tissues from control and diabetic rats: modulatory effects of a PPARγ agonist on nitridergic and lipid placental metabolism

2005 ◽  
Vol 17 (4) ◽  
pp. 423 ◽  
Author(s):  
E. Capobianco ◽  
A. Jawerbaum ◽  
M. C. Romanini ◽  
V. White ◽  
C. Pustovrh ◽  
...  
Keyword(s):  
De Novo ◽  
Lipid Synthesis ◽  
Diabetic Rats ◽  
Lipid Homeostasis ◽  
Diabetic Rat ◽  
No Production ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Prostaglandin J2

15-Deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) is a peroxisome proliferator-activated receptor γ (PPARγ) ligand that regulates lipid homeostasis and has anti-inflammatory properties in many cell types. We postulated that 15dPGJ2 may regulate lipid homeostasis and nitric oxide (NO) levels in term placental tissues and that alterations in these pathways may be involved in diabetes-induced placental derangements. In the present study, we observed that, in term placental tissues from streptozotocin-induced diabetic rats, 15dPGJ2 concentrations were decreased (83%) and immunostaining for nitrotyrosine, indicating peroxynitrite-induced damage, was increased. In the presence of 15dPGJ2, concentrations of nitrates/nitrites (an index of NO production) were diminished (40%) in both control and diabetic rats, an effect that seems to be both dependent on and independent of PPARγ activation. Exogenous 15dPGJ2 did not modify lipid mass, but decreased the incorporation of 14C-acetate into triacylglycerol (35%), cholesteryl ester (55%) and phospholipid (32%) in placenta from control rats, an effect that appears to be dependent on PPARγ activation. In contrast, the addition of 15dPGJ2 did not alter de novo lipid synthesis in diabetic rat placenta, which showed decreased levels of PPARγ. We conclude that 15dPGJ2 modulates placental lipid metabolism and NO production. The concentration and function of 15dPGJ2 and concentrations of PPARγ were altered in placentas from diabetic rats, anomalies probably involved in diabetes-induced placental dysfunction.

AT1-receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats

2008 ◽  
Vol 45 (5) ◽  
pp. 619-626 ◽  
Author(s):  
Philip Wenzel ◽  
Eberhard Schulz ◽  
Matthias Oelze ◽  
Johanna Müller ◽  
Swenja Schuhmacher ◽  
...  
Keyword(s):  
Diabetic Rats ◽  
At1 Receptor ◽  
Receptor Blockade ◽  
Gtp Cyclohydrolase I ◽  
Gtp Cyclohydrolase

scholarly journals cGMP Inhibits GTP Cyclohydrolase I Activity and Biosynthesis of Tetrahydrobiopterin in Human Umbilical Vein Endothelial Cells

2003 ◽  
Vol 93 (3) ◽  
pp. 265-271 ◽  
Author(s):  
Hiroaki Shiraishi ◽  
Taiya Kato ◽  
Koji Atsuta ◽  
Chiho Sumi-Ichinose ◽  
Masatsugu Ohtsuki ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Gtp Cyclohydrolase I ◽  
Gtp Cyclohydrolase ◽  
Human Umbilical Vein ◽  
Umbilical Vein Endothelial Cells
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