General Information:

Id: 2,083
Diseases: Diabetes mellitus, type II - [OMIM]
Insulin resistance
Bos taurus
BTO:0003247 BAEC cell
article
Reference: Nishikawa T et al.(2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404: 787-790 [PMID: 10783895]

Interaction Information:

Comment Hyperglycaemia increases the production of reactive oxygen species inside cultured bovine aortic endothelial cells.
Formal Description
Interaction-ID: 16799

phenotype

hyperglycemia

increases_quantity of

drug/chemical compound

Reactive oxygen species

Comment The TCA cycle is the source of increased ROS-generating substrate induced by hyperglycaemia.
Formal Description
Interaction-ID: 16809

phenotype

hyperglycemia

affects_activity of

Comment The TCA cycle is the source of increased ROS-generating substrate induced by hyperglycaemia.
Formal Description
Interaction-ID: 16810

increases_quantity of

drug/chemical compound

Reactive oxygen species

Comment To determine the site of hyperglycaemia-induced intracellular ROS production, bovine aortic endothelial cells were first incubated with either rotenone, an inhibitor of complex I, thenoyltrifluoroacetone (TTFA), an inhibitor of complex II, or carbonyl cyanide m-chlorophenylhydrazone (CCCP), an uncoupler of oxidative phosphorylation that abolishes the mitochondrial membrane proton gradient. Rotenone did not reduce this increased ROS production, whereas both TTFA and CCCP completely prevented the effect of hyperglycaemia.
Formal Description
Interaction-ID: 16811

complex/PPI

Mitochondrial respiratory chain complex I

NOT affects_quantity of

drug/chemical compound

Reactive oxygen species

if induced by hyperglycemia
Comment To determine the site of hyperglycaemia-induced intracellular ROS production, bovine aortic endothelial cells were first incubated with either rotenone, an inhibitor of complex I, thenoyltrifluoroacetone (TTFA), an inhibitor of complex II, or carbonyl cyanide m-chlorophenylhydrazone (CCCP), an uncoupler of oxidative phosphorylation that abolishes the mitochondrial membrane proton gradient. Rotenone did not reduce this increased ROS production, whereas both TTFA and CCCP completely prevented the effect of hyperglycaemia.
Formal Description
Interaction-ID: 16812

complex/PPI

Mitochondrial respiratory chain complex II

increases_quantity of

drug/chemical compound

Reactive oxygen species

if induced by hyperglycemia
Comment To determine the site of hyperglycaemia-induced intracellular ROS production, bovine aortic endothelial cells were first incubated with either rotenone, an inhibitor of complex I, thenoyltrifluoroacetone (TTFA), an inhibitor of complex II, or carbonyl cyanide m-chlorophenylhydrazone (CCCP), an uncoupler of oxidative phosphorylation that abolishes the mitochondrial membrane proton gradient. Rotenone did not reduce this increased ROS production, whereas both TTFA and CCCP completely prevented the effect of hyperglycaemia.
Formal Description
Interaction-ID: 16813

increases_quantity of

drug/chemical compound

Reactive oxygen species

if induced by hyperglycemia
Comment Overexpression of uncoupling protein-1 (UCP1), a specifc protein uncoupler of oxidative phosphorylation capable of collapsing the proton electrochemical gradient, also prevented the effect of hyperglycaemia.
Formal Description
Interaction-ID: 16814

gene/protein

UCP1

NOT increases_quantity of

drug/chemical compound

Reactive oxygen species

if UCP1 is overexpressed and if induced by hyperglycemia
Comment Overexpression of manganese superoxide dismutase (Mn-SOD), the mitochondrial form of this antioxidant enzyme, also prevented the effect of hyperglycaemia. This result shows that superoxide is the reactive oxygen radical produced by this mechanism.
Formal Description
Interaction-ID: 16815

gene/protein

SOD2

NOT increases_quantity of

drug/chemical compound

Reactive oxygen species

if SOD2 is overexpressed and if induced by hyperglycemia
Drugbank entries Show/Hide entries for SOD2
Comment Activation of protein kinase C (PKC) appears to be important in the pathogenesis of diabetic complications. Therefore, we tested the effects of TTFA, CCCP, UCP1 and manganese superoxide dismutase on hyperglycaemia-induced activation of PKC. Each completely inhibited PKC activation, indicating that mitochondrial superoxide overproduction may initiate the hyperglycaemia-induced de novo synthesis of diacylglycerol or phosphatidylcholine hydrolysis that activates PKC.
Formal Description
Interaction-ID: 16816

drug/chemical compound

Reactive oxygen species

increases_activity of

gene/protein

Protein kinase C

Comment Excessive production of advanced glycation end-products (AGEs) also appears to be important in the pathogenesis of diabetic complications. Normalizing levels of mitochondrial reactive oxygen species prevents formation of advanced glycation end-products.
Formal Description
Interaction-ID: 16817

drug/chemical compound

Reactive oxygen species

increases_quantity of

drug/chemical compound

Advanced glycation end-product

Comment Increased flux through the polyol pathway is a third mechanism that appears to be important in the pathogenesis of diabetic complications. In this pathway, elevated glucose concentration results in increased production of sorbitol by the enzyme aldose reductase. Hyperglycaemia-induced sorbitol accumulation was completely prevented by TTFA, UCP1 and Mn-SOD, indicating that mitochondrial superoxide overproduction stimulates aldose reductase activity.
Formal Description
Interaction-ID: 16818

drug/chemical compound

Reactive oxygen species

increases_activity of

gene/protein

AKR1B1

Drugbank entries Show/Hide entries for AKR1B1
Comment Increased flux through the polyol pathway is a third mechanism that appears to be important in the pathogenesis of diabetic complications. In this pathway, elevated glucose concentration results in increased production of sorbitol by the enzyme aldose reductase. Hyperglycaemia-induced sorbitol accumulation was completely prevented by TTFA, UCP1 and Mn-SOD, indicating that mitochondrial superoxide overproduction stimulates aldose reductase activity.
Formal Description
Interaction-ID: 16819

drug/chemical compound

Reactive oxygen species

increases_quantity of

drug/chemical compound

Sorbitol

Comment Increased flux through the polyol pathway is a third mechanism that appears to be important in the pathogenesis of diabetic complications. In this pathway, elevated glucose concentration results in increased production of sorbitol by the enzyme aldose reductase. Hyperglycaemia-induced sorbitol accumulation was completely prevented by TTFA, UCP1 and Mn-SOD, indicating that mitochondrial superoxide overproduction stimulates aldose reductase activity.
Formal Description
Interaction-ID: 16820

drug/chemical compound

Reactive oxygen species

increases_activity of

process

polyol pathway

Comment Hyperglycaemia also activates NF-kappaB, in part by activation of PKC. Glucose activates endothelial cell NFkB by inducing overproduction of mitochondrial superoxide.
Formal Description
Interaction-ID: 16821

drug/chemical compound

Reactive oxygen species

increases_activity of

complex/PPI

NF-kappaB complex