| Role of EDHF in type 2 diabetes-induced endothelial dysfunction. | |
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MedLine Citation:
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PMID: 18790831 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Endothelium-derived hyperpolarizing factor (EDHF) plays a crucial role in modulating vasomotor tone, especially in microvessels when nitric oxide-dependent control is compromised such as in diabetes. Epoxyeicosatrienoic acids (EETs), potassium ions (K+), and hydrogen peroxide (H2O2) are proposed as EDHFs. However, the identity (or identities) of EDHF-dependent endothelial dilators has not been clearly elucidated in diabetes. We assessed the mechanisms of EDHF-induced vasodilation in wild-type (WT, normal), db/db (advanced type 2 diabetic) mice, and db/db mice null for TNF (dbTNF-/dbTNF-). In db/db mice, EDHF-induced vasodilation [ACh-induced vasodilation in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME, 10 micromol/l) and prostaglandin synthase inhibitor indomethacin (Indo, 10 mumol/l)] was diminished after the administration of catalase (an enzyme that selectively dismutates H2O2 to water and oxygen, 1,000 U/ml); administration of the combination of charybdotoxin (a nonselective blocker of intermediate-conductance Ca2+-activated K+ channels, 10 micromol/l) and apamin (a selective blocker of small-conductance Ca2+-activated K+ channels, 50 micromol/l) also attenuated EDHF-induced vasodilation, but the inhibition of EETs synthesis [14,15-epoxyeicosa-5(Z)-enoic acid; 10 mumol/l] did not alter EDHF-induced vasodilation. In WT controls, EDHF-dependent vasodilation was significantly diminished after an inhibition of K+ channel, EETs synthesis, or H2O2 production. Our molecular results indicate that mRNA and protein expression of interleukin-6 (IL-6) were greater in db/db versus WT and dbTNF-/dbTNF- mice, but neutralizing antibody to IL-6 (anti-IL-6; 0.28 mg.ml(-1).kg(-1) ip for 3 days) attenuated IL-6 expression in db/db mice. The incubation of the microvessels with IL-6 (5 ng/ml) induced endothelial dysfunction in the presence of l-NAME and Indo in WT mice, but anti-IL-6 restored ACh-induced vasodilation in the presence of L-NAME and Indo in db/db mice. In db(TNF-)/db(TNF-) mice, EDHF-induced vasodilation was greater and comparable with controls, but IL-6 decreased EDHF-mediated vasodilation. Our results indicate that EDHF compensates for diminished NO-dependent dilation in IL-6-induced endothelial dysfunction by the activation of H2O2 or a K+ channel in type 2 diabetes. |
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Authors:
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Yoonjung Park; Stefano Capobianco; Xue Gao; John R Falck; Kevin C Dellsperger; Cuihua Zhang |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-09-12 |
Journal Detail:
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Title: American journal of physiology. Heart and circulatory physiology Volume: 295 ISSN: 0363-6135 ISO Abbreviation: Am. J. Physiol. Heart Circ. Physiol. Publication Date: 2008 Nov |
Date Detail:
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Created Date: 2008-11-10 Completed Date: 2008-12-22 Revised Date: 2010-09-21 |
Medline Journal Info:
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Nlm Unique ID: 100901228 Medline TA: Am J Physiol Heart Circ Physiol Country: United States |
Other Details:
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Languages: eng Pagination: H1982-8 Citation Subset: IM |
Affiliation:
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Department of Internal Medicine, Medical Pharmacology and Physiology and Nutritional Science, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO 65211, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Arterioles / metabolism, physiopathology Biological Factors / metabolism* Blood Glucose / metabolism Body Weight Coronary Vessels / metabolism, physiopathology Cyclooxygenase Inhibitors / pharmacology Diabetes Mellitus, Type 2 / metabolism*, physiopathology Disease Models, Animal Dose-Response Relationship, Drug Endothelium, Vascular / drug effects, metabolism*, physiopathology Female Hydrogen Peroxide / metabolism Interleukin-6 / genetics, metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Nitric Oxide / metabolism Nitric Oxide Synthase / antagonists & inhibitors, metabolism Potassium Channel Blockers / pharmacology Potassium Channels / metabolism RNA, Messenger / metabolism Tumor Necrosis Factor-alpha / genetics, metabolism Vasodilation* / drug effects Vasodilator Agents / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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R01-HL-077566/HL/NHLBI NIH HHS; R01-HL-085119/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Biological Factors; 0/Blood Glucose; 0/Cyclooxygenase Inhibitors; 0/Interleukin-6; 0/Potassium Channel Blockers; 0/Potassium Channels; 0/RNA, Messenger; 0/Tumor Necrosis Factor-alpha; 0/Vasodilator Agents; 0/endothelium-dependent hyperpolarization factor; 10102-43-9/Nitric Oxide; 7722-84-1/Hydrogen Peroxide; EC 1.14.13.39/Nitric Oxide Synthase |
| Comments/Corrections | |
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