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Aortic superoxide production at the early hyperglycemic stage in a rat type 2 diabetes model and the effects of pravastatin
- Source :
- Biologicalpharmaceutical bulletin. 37(6)
- Publication Year :
- 2014
-
Abstract
- Endothelium-derived superoxide induces vascular dysfunctions. The aim of this study was to examine the activity of protein kinase C (PKC) isoforms and endothelial nitric oxide synthase (eNOS), which leads to vascular superoxide production in type 2 diabetes, in addition to the effects of pravastatin. We studied these mechanisms in Otsuka Long-Evans Tokushima Fatty (OLETF) rats (type 2 diabetes model) at the early hyperglycemic stage (vs. non-diabetic Long-Evans Tokushima Otsuka [LETO] rats). Superoxide production and catalase activity were measured in aortas, as were the protein expressions of PKCδ and phospho-Ser(1177) eNOS. Superoxide production was increased in OLETF rats, and this increase was inhibited by the selective conventional PKC (cPKC) inhibitor Go6976 and by the non-selective cPKC and novel PKC inhibitor GF109203X. Phospho-Ser(1177) eNOS was significantly increased in OLETF rats, whereas the protein expressions of PKCδ and phosopho-Thr(505) PKCδ and catalase activity were all greatly reduced. Pravastatin administration to OLETF rats in vivo had normalizing effects on all of these variables. The increment in superoxide production seen in OLETF rats (but not the production in pravastatin-treated OLETF rats) was abolished by high concentration of N(ω)-nitro-L-arginine methyl ester (electron transport inhibitor of eNOS), by sepiapterin (precursor of tetrahydrobiopterin), and by LY294002 (phosphatidylinositol 3-kinase [PI3-kinase] inhibitor). In OLETF rats at the early hyperglycemic stage, aortic superoxide production is increased owing to activation of uncoupled eNOS through phosphorylation by PI3-kinase/Akt. This may be related to the observed reduction in PKCδ/catalase activities. Pravastatin inhibited endothelial superoxide production via normalization of PKCδ/catalase activities.
- Subjects :
- Blood Glucose
Male
medicine.medical_specialty
Sepiapterin
Nitric Oxide Synthase Type III
Pharmaceutical Science
Coronary Disease
Diabetes Mellitus, Experimental
chemistry.chemical_compound
Enos
Superoxides
Internal medicine
medicine
Animals
LY294002
Rats, Long-Evans
Enzyme Inhibitors
Protein kinase C
Aorta
Protein Kinase C
Pravastatin
Pharmacology
biology
Chemistry
Superoxide
General Medicine
Tetrahydrobiopterin
biology.organism_classification
Catalase
Endocrinology
Diabetes Mellitus, Type 2
biology.protein
Endothelium, Vascular
Hydroxymethylglutaryl-CoA Reductase Inhibitors
medicine.drug
Subjects
Details
- ISSN :
- 13475215
- Volume :
- 37
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Biologicalpharmaceutical bulletin
- Accession number :
- edsair.doi.dedup.....454e6b5dd34e24eec1de8aba99ef42cc