title: Role of EDHF in type 2 diabetes-induced endothelial dysfunction.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Medical Pharmacology and Physiology and Nutritional Science, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO 65211, USA.
authors.forename: Yoonjung
authors.initials: Y
authors.lastname: Park
authors.forename: Stefano
authors.initials: S
authors.lastname: Capobianco
authors.forename: Xue
authors.initials: X
authors.lastname: Gao
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Dellsperger
authors.forename: Cuihua
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000503:physiopathology; D001685:Biological Factors / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003331:Coronary Vessels / Q000378:metabolism / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001685:Biological Factors; D001786:Blood Glucose; D016861:Cyclooxygenase Inhibitors; D015850:Interleukin-6; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase
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