3 ',4 '-Dihydroxyflavonol reduces superoxide and improves nitric oxide function in diabetic rat mesenteric arteries

Leo, C, Hart, J and Woodman, O 2011, '3 ',4 '-Dihydroxyflavonol reduces superoxide and improves nitric oxide function in diabetic rat mesenteric arteries', Plos one, vol. 6, no. 6, pp. 1-11.


Document type: Journal Article
Collection: Journal Articles

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Title 3 ',4 '-Dihydroxyflavonol reduces superoxide and improves nitric oxide function in diabetic rat mesenteric arteries
Author(s) Leo, C
Hart, J
Woodman, O
Year 2011
Journal name Plos one
Volume number 6
Issue number 6
Start page 1
End page 11
Total pages 11
Publisher Public Library of Science
Abstract Background: 3',4'-Dihydroxyflavonol (DiOHF) is an effective antioxidant that acutely preserves nitric oxide (NO) activity in the presence of elevated reactive oxygen species (ROS). We hypothesized that DiOHF treatment (7 days, 1 mg/kg per day s.c.) would improve relaxation in mesenteric arteries from diabetic rats where endothelial dysfunction is associated with elevated oxidant stress. Methodology/Principal Findings: In mesenteric arteries from diabetic rats there was an increase in ROS, measured by L-012 and 2',7'-dichlorodihydrofluorescein diacetate fluorescence. NADPH oxidase-derived superoxide levels, assayed by lucigenin chemiluminescence, were also significantly increased in diabetic mesenteric arteries (diabetes, 4892±946 counts/mg versus normal 2486±344 counts/mg, n = 7–10, p<0.01) associated with an increase in Nox2 expression but DiOHF (2094±300 counts/mg, n = 10, p<0.001) reversed that effect. Acetylcholine (ACh)-induced relaxation of mesenteric arteries was assessed using wire myography (pEC50 = 7.94±0.13 n = 12). Diabetes significantly reduced the sensitivity to ACh and treatment with DiOHF prevented endothelial dysfunction (pEC50, diabetic 6.86±0.12 versus diabetic+DiOHF, 7.49±0.13, n = 11, p<0.01). The contribution of NO versus endothelium-derived hyperpolarizing factor (EDHF) to ACh-induced relaxation was assessed by evaluating responses in the presence of TRAM-34+apamin+iberiotoxin or N-nitro-L-arginine+ODQ respectively. Diabetes impaired the contribution of both NO (maximum relaxation, Rmax diabetic 24±7 versus normal, 68±10, n = 9–10, p<0.01) and EDHF (pEC50, diabetic 6.63±0.15 versus normal, 7.14±0.12, n = 10–11, p<0.01) to endothelium-dependent relaxation. DiOHF treatment did not significantly affect the EDHF contribution but enhanced NO-mediated relaxation (Rmax 69±6, n = 11, p<0.01). Western blotting demonstrated that diabetes also decreased expression and increased uncoupling of endothelial NO synthase (eNOS). Treatment of the diabetic rats with DiOHF significantly reduced vascular ROS and restored NO-mediated endothelium-dependent relaxation. Treatment of the diabetic rats with DiOHF also increased eNOS expression, both in total and as a dimer. Conclusions/Significance: DiOHF improves NO activity in diabetes by reducing Nox2-dependent superoxide production and preventing eNOS uncoupling to improve endothelial function.
Subject Cardiology (incl. Cardiovascular Diseases)
Endocrinology
Basic Pharmacology
Keyword(s) 3'
4' dihydroxyflavonol
acetylcholine
endothelial nitric oxide synthase
endothelium derived hyperpolarizing factor
flavonol derivative
nitric oxide
reactive oxygen metabolite
reduced nicotinamide adenine dinucleotide phosphate oxidase 2
superoxide
unclassified drug
animal experiment
animal model
animal tissue
antioxidant activity
article
controlled study
diabetes mellitus
drug mechanism
drug sensitivity
endothelial dysfunction
male
mesenteric artery
nonhuman
protein expression
rat
vasodilatationCHEMICALS/CAS: acetylcholine
51-84-3
60-31-1
66-23-9
endothelial nitric oxide synthase
503473-02-7
endothelium derived hyperpolarizing factor
116788-37-5
nitric oxide
10102-43-9
superoxide
11062-77-4
DOI - identifier 10.1371/journal.pone.0020813
Copyright notice © 2011 Leo et al.
ISSN 1932-6203
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Citation counts: TR Web of Science Citation Count  Cited 27 times in Thomson Reuters Web of Science Article | Citations
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