Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) synthesis in endothelial cells is impaired in diabetes. We previously showed that impaired NO synthesis in the spontaneously diabetic BB (BBd) rat is due to decreased levels of tetrahydrobiopterin (BH4), secondary to decreased expression of GTP cyclohydrolase I (GTPCH). The aim of this study was to utilize adenoviral GTPCH gene transfer to reverse BH4 deficiency and repair the ability of endothelial cells to produce NO. GTPCH gene transfer increased BH4 levels in BBd endothelial cells from 0.17 +/- 0.02 (mean +/-SE) to 73.37 +/- 14.42 pmol/million cells and NO production from 0.77 +/- 0.07 to 18.74 +/- 5.52 nmol/24 h/million cells. To demonstrate a functional effect of increasing BH4 concentrations in tissues, we transferred GTPCH into aortic rings from BBd and Zucker diabetic fatty (ZDF) rats, models of human type I and type II diabetes, respectively. GTPCH gene transfer led to a dose-dependent increase in acetylcholine-induced vasorelaxation, preventable by inhibiting NO synthase. Maximal relaxation of virus-treated rings (10(10) virus particles/ml) to acetylcholine was significantly higher than sham-treated rings (BBd 64% vs. 37%, P<0.005; ZDF 80% vs. 44%, P<0.05). This study demonstrates that GTPCH gene transfer can reverse BH4 deficiency in both type I and type II diabetes and provides an experimental basis for using gene therapy to treat cardiovascular complications in diabetic patients.
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PMID:GTP cyclohydrolase I gene transfer reverses tetrahydrobiopterin deficiency and increases nitric oxide synthesis in endothelial cells and isolated vessels from diabetic rats. 1546 10

Watermelon is rich in L-citrulline, an effective precursor of L-arginine. This study was conducted to determine whether dietary supplementation with watermelon pomace juice could ameliorate the metabolic syndrome in the Zucker diabetic fatty (ZDF) rat, an animal model of noninsulin-dependent diabetes mellitus. Nine-week-old ZDF rats were assigned randomly to receive drinking water containing 0% (control) or 0.2% L-arginine (as 0.24% L-arginine-HCl), 63% watermelon pomace juice, 0.01% lycopene, or 0.05% citrus pectin (n = 6 per treatment). At the end of the 4-wk supplementation period, blood samples, aortic rings, and hearts were obtained for biochemical and physiological analyses. Feed or energy intakes did not differ among the 5 groups of rats. However, dietary supplementation with watermelon pomace juice or L-arginine increased serum concentrations of arginine; reduced fat accretion; lowered serum concentrations of glucose, free fatty acids, homocysteine, and dimethylarginines; enhanced GTP cyclohydrolase-I activity and tetrahydrobiopterin concentrations in the heart; and improved acetylcholine-induced vascular relaxation. Compared with the control, dietary supplementation with lycopene or citrus pectin did not affect any measured parameter. These results provide the first evidence to our knowledge for a beneficial effect of watermelon pomace juice as a functional food for increasing arginine availability, reducing serum concentrations of cardiovascular risk factors, improving glycemic control, and ameliorating vascular dysfunction in obese animals with type-II diabetes.
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PMID:Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the metabolic syndrome in Zucker diabetic fatty rats. 1802 83

1. Oxidative stress contributes to endothelial dysfunction and atherogenesis in diabetes. The present study tested the hypothesis that a high-cholesterol diet accelerates endothelial dysfunction in Ins2(Akita) mice, a Type 1 diabetic model with a spontaneous autosomal preproinsulin gene (Ins2 gene) mutation, through further increase of superoxide production. 2. The Ins2(Akita) diabetic mice were fed a high-cholesterol diet (1.25% cholesterol) for 4 months. Some Ins2(Akita) mice were also treated for 4 months with the selective NADPH oxidase inhibitor apocynin (4 mg/kg per day in drinking water). Oxidative stress markers, tetrahydrobiopterin (BH4) levels, GTP cyclohydrolase I activity and endothelial function were determined in serum or arteries afterwards. 3. Serum lipid peroxidation and arterial superoxide levels were increased, whereas arterial BH(4) levels and GTP cyclohydrolase I activity were decreased, in Ins2(Akita) mice on a high-cholesterol diet, resulting in impaired endothelium-dependent nitric oxide-mediated relaxation in response to acetylcholine. 4. In vivo treatment with apocynin not only blunted serum lipid peroxidation and arterial superoxide levels, but also increased BH4 levels and GTP cyclohydrolase I activity, resulting in improved endothelium-dependent relaxation. 5. These results suggest that NADPH oxidase may play a potential role in oxidative stress-induced arterial BH4 and GTP cyclohydrolase I deficiency, resulting in endothelial dysfunction in Ins2(Akita) Type 1 diabetic mice fed a high-cholesterol diet.
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PMID:High-cholesterol diet augments endothelial dysfunction via elevated oxidative stress and reduced tetrahydrobiopterin in Ins2(Akita) mice, an autosomal dominant mutant type 1 diabetic model. 1920 18

Tetrahydrobiopterin (BH4) is a key redox-active cofactor in endothelial isoform of NO synthase (eNOS) catalysis and is an important determinant of NO-dependent signaling pathways. BH4 oxidation is observed in vascular cells in the setting of the oxidative stress associated with diabetes. However, the relative roles of de novo BH4 synthesis and BH4 redox recycling in the regulation of eNOS bioactivity remain incompletely defined. We used small interference RNA (siRNA)-mediated "knockdown" GTP cyclohydrolase-1 (GTPCH1), the rate-limiting enzyme in BH4 biosynthesis, and dihydrofolate reductase (DHFR), an enzyme-recycling oxidized BH4 (7,8-dihydrobiopterin (BH2)), and studied the effects on eNOS regulation and biopterin metabolism in cultured aortic endothelial cells. Knockdown of either DHFR or GTPCH1 attenuated vascular endothelial growth factor (VEGF)-induced eNOS activity and NO production; these effects were recovered by supplementation with BH4. In contrast, supplementation with BH2 abolished VEGF-induced NO production. DHFR but not GTPCH1 knockdown increased reactive oxygen species (ROS) production. The increase in ROS production seen with siRNA-mediated DHFR knockdown was abolished either by simultaneous siRNA-mediated knockdown of eNOS or by supplementing with BH4. In contrast, addition of BH2 increased ROS production; this effect of BH2 was blocked by BH4 supplementation. DHFR but not GTPCH1 knockdown inhibited VEGF-induced dephosphorylation of eNOS at the inhibitory site serine 116; these effects were recovered by supplementation with BH4. These studies demonstrate a striking contrast in the pattern of eNOS regulation seen by the selective modulation of BH4 salvage/reduction versus de novo BH4 synthetic pathways. Our findings suggest that the depletion of BH4 is not sufficient to perturb NO signaling, but rather that concentration of intracellular BH2, as well as the relative concentrations of BH4 and BH2, together play a determining role in the redox regulation of eNOS-modulated endothelial responses.
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PMID:Tetrahydrobiopterin recycling, a key determinant of endothelial nitric-oxide synthase-dependent signaling pathways in cultured vascular endothelial cells. 1928 67

Obesity and type-II diabetes are growing major health issues worldwide. They are the leading risk factors for vascular insulin resistance, which plays an important role in the pathogenesis of cardiovascular disease, the leading cause of death in developed nations. Recent studies have shown that reduced synthesis of nitric oxide (NO; a major vasodilator) from L-arginine in endothelial cells is a major factor contributing to the impaired action of insulin in the vasculature of obese and diabetic subjects. The decreased NO generation results from a deficiency of (6R)-5,6,7,8-tetrahydrobiopterin [BH4; an essential cofactor for NO synthase (NOS)], as well as increased generation of glucosamine (an inhibitor of the pentose cycle for the production of NADPH, another cofactor for NOS) from glucose and L-glutamine. Accordingly, endothelial dysfunction can be prevented by (1) enhancement of BH4 synthesis through supplementation of its precursor (sepiapterin) via the salvage pathway; (2) transfer of the gene for GTP cyclohydrolase-I (the first and key regulatory enzyme for de novo synthesis of BH4); or (3) dietary supplementation of L-arginine (which stimulates GTP cyclohydrolase-I expression and inhibits hexosamine production). Modulation of the arginine-NO pathway by BH4 and arginine is beneficial for ameliorating vascular insulin resistance in obesity and diabetes.
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PMID:Nitric oxide and vascular insulin resistance. 1931 42

Refractory wound is a severe complication that leads to limb amputation in diabetes. Endothelial nitric oxide synthase (eNOS) plays a key role in normal wound repair but is uncoupled in streptozotocin (STZ)-induced type 1 diabetes because of reduced cofactor tetrahydrobiopterin (BH(4)). We tested the hypothesis that overexpression of GTP cyclohydrolase I (GTPCH I), the rate-limiting enzyme for de novo BH(4) synthesis, retards NOS uncoupling and accelerates wound healing in STZ mice. Blood glucose levels were significantly increased in both male endothelium-specific GTPCH I transgenic mice (Tg-GCH; via a tie-2 promoter) and wild-type (WT) littermates 5 days after STZ regimen. A full-thickness excisional wound was created on mouse dorsal skin by a 4-mm punch biopsy. Wound closure was delayed in STZ mice, which was rescued in STZ Tg-GCH mice. Cutaneous BH(4) level was significantly reduced in STZ mice vs. WT mice, which was maintained in STZ Tg-GCH mice. In STZ mice, constitutive NOS (cNOS) activity and nitrite levels were decreased compared with WT mice, paralleled by increased superoxide anion (O(2)(-)) level and inducible NOS (iNOS) activity. In STZ Tg-GCH mice, nitrite level and cNOS activity were potentiated and O(2)(-) level and iNOS activity were suppressed compared with STZ mice. Thus endothelium-specific BH(4) overexpression accelerates wound healing in type 1 diabetic mice by enhancing cNOS activity and suppressing oxidative stress.
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PMID:Endothelium-specific GTP cyclohydrolase I overexpression accelerates refractory wound healing by suppressing oxidative stress in diabetes. 1933 62

Tetrahydrobiopterin (BH(4)) is a critical cofactor for the nitric oxide synthases. In the absence of BH(4), these enzymes become uncoupled, fail to produce nitric oxide, and begin to produce superoxide and other reactive oxygen species (ROS). BH(4) levels are modulated by a complex biosynthetic pathway, salvage enzymes, and by oxidative degradation. The enzyme GTP cyclohydrolase-1 catalyzes the first step in the de novo synthesis of BH(4) and new evidence shows that this enzyme is regulated by phosphorylation, which reduces its interaction with its feedback regulatory protein (GFRP). In the setting of a variety of common diseases, such as atherosclerosis, hypertension, and diabetes, reactive oxygen species promote oxidation of BH(4) and inhibit expression of the salvage enzyme dihydrofolate reductase (DHFR), promoting accumulation of BH(2) and NOS uncoupling. There is substantial interest in therapeutic approaches to increasing tissue levels of BH(4), largely by oral administration of this agent. BH(4) treatment has proved effective in decreasing atherosclerosis, reducing blood pressure, and preventing complications of diabetes in experimental animals. While these basic studies have been very promising, there are only a few studies showing any effect of BH(4) therapy in humans in treatment of these common problems. Whether BH(4) or related agents will be useful in treatment of human diseases needs additional study.
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PMID:Regulation of endothelial cell tetrahydrobiopterin pathophysiological and therapeutic implications. 2108 Dec 17

BH4 (6R-L-erythro-5,6,7,8-tetrahydrobiopterin) is an essential cofactor of a set of enzymes that are of central metabolic importance, including four aromatic amino acid hydroxylases, alkylglycerol mono-oxygenase and three NOS (NO synthase) isoenzymes. Consequently, BH4 is present in probably every cell or tissue of higher organisms and plays a key role in a number of biological processes and pathological states associated with monoamine neurotransmitter formation, cardiovascular and endothelial dysfunction, the immune response and pain sensitivity. BH4 is formed de novo from GTP via a sequence of three enzymatic steps carried out by GTP cyclohydrolase I, 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. An alternative or salvage pathway involves dihydrofolate reductase and may play an essential role in peripheral tissues. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase, except for NOSs, in which the BH4 cofactor undergoes a one-electron redox cycle without the need for additional regeneration enzymes. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I. BH4 biosynthesis is controlled in mammals by hormones and cytokines. BH4 deficiency due to autosomal recessive mutations in all enzymes, except for sepiapterin reductase, has been described as a cause of hyperphenylalaninaemia. A major contributor to vascular dysfunction associated with hypertension, ischaemic reperfusion injury, diabetes and others, appears to be an effect of oxidized BH4, which leads to an increased formation of oxygen-derived radicals instead of NO by decoupled NOS. Furthermore, several neurological diseases have been suggested to be a consequence of restricted cofactor availability, and oral cofactor replacement therapy to stabilize mutant phenylalanine hydroxylase in the BH4-responsive type of hyperphenylalaninaemia has an advantageous effect on pathological phenylalanine levels in patients.
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PMID:Tetrahydrobiopterin: biochemistry and pathophysiology. 2186 84

The current study investigated the potential of green tea (GT) to improve uncoupling of endothelial nitric oxide synthase (eNOS) in diabetic conditions. In rats with streptozotocin-induced diabetes, nitric oxide (NO) bioavailability was reduced by uncoupling eNOS, characterized by a reduction in tetrahydrobiopterin (BH(4)) levels and a decrease in the eNOS dimer-to-monomer ratio. GT treatment ameliorated these abnormalities. Moreover, immortalized human mesangial cells (ihMCs) exposed to high glucose (HG) levels exhibited a rise in reactive oxygen species (ROS) and a decline in NO levels, which were reversed with GT. BH(4) and the activity of guanosine triphosphate cyclohydrolase I decreased in ihMCs exposed to HG and was normalized by GT. Exogenous administration of BH(4) in ihMCs reversed the HG-induced rise in ROS and the decline in NO production. However, coadministration of GT with BH(4) did not result in a further reduction in ROS production, suggesting that reduced ROS with GT was indeed secondary to uncoupled eNOS. In summary, GT reversed the diabetes-induced reduction of BH(4) levels, ameliorating uncoupling eNOS, and thus increasing NO bioavailability and reducing oxidative stress, two abnormalities that are involved in the pathogenesis of diabetic nephropathy.
Diabetes 2012 Jul
PMID:Uncoupling endothelial nitric oxide synthase is ameliorated by green tea in experimental diabetes by re-establishing tetrahydrobiopterin levels. 2258 83

In diabetes, endothelial nitric oxide synthase (eNOS) produces superoxide anion rather than nitric oxide, referred to as "eNOS uncoupling," which may contribute to endothelial dysfunction, albuminuria, and diabetic nephropathy. Reduced levels of endothelium-derived tetrahydrobiopterin (BH4), an essential cofactor for eNOS, promote eNOS uncoupling. Accelerated degradation of guanosine triphosphate cyclohydrolase I (GTPCH I), the rate-limiting enzyme in BH4 biosynthesis, also occurs in diabetes, suggesting that GTPCH I may have a role in diabetic microvascular disease. Here, we crossed endothelium-dominant GTPCH I transgenic mice with Ins2(+/Akita) diabetic mice and found that endothelial overexpression of GTPCH I led to higher levels of intrarenal BH4 and lower levels of urinary albumin and reactive oxygen species compared with diabetic control mice. Furthermore, GTPCH I overexpression attenuated the hyperpermeability of macromolecules observed in diabetic control mice. In addition, we treated Ins2(+/Akita) mice with metformin, which activates AMP-activated protein kinase (AMPK) and thereby slows the degradation of GTPCH I; despite blood glucose levels that were similar to untreated mice, those treated with metformin had significantly less albuminuria. Similarly, in vitro, treating human glomerular endothelial cells with AMPK activators attenuated glucose-induced reductions in phospho-AMPK, GTPCH I, and coupled eNOS. Taken together, these data suggest that maintenance of endothelial GTPCH I expression and the resulting improvement in BH4 biosynthesis ameliorate diabetic nephropathy.
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PMID:Maintenance of endothelial guanosine triphosphate cyclohydrolase I ameliorates diabetic nephropathy. 2362 Mar 95


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