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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/H1982    most recent 01261.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Park, Y. Articles by Zhang, C. PubMed PubMed Citation Articles by Park, Y. Articles by Zhang, C.

Role of EDHF in type 2 diabetes-induced endothelial dysfunction

¹Departments of Internal Medicine, Medical Pharmacology and Physiology and Nutritional Sciences, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri; and ²Department of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas

Submitted 30 October 2007 ; accepted in final form 25 August 2008

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 (db^TNF–/db^TNF–). In db/db mice, EDHF-induced vasodilation [ACh-induced vasodilation in the presence of N^G-nitro-L-arginine methyl ester (L-NAME, 10 µmol/l) and prostaglandin synthase inhibitor indomethacin (Indo, 10 µmol/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 µmol/l) and apamin (a selective blocker of small-conductance Ca²⁺-activated K⁺ channels, 50 µmol/l) also attenuated EDHF-induced vasodilation, but the inhibition of EETs synthesis [14,15-epoxyeicosa-5(Z)-enoic acid; 10 µmol/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 db^TNF–/db^TNF– 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.

acetylcholine; coronary disease; endothelium; microcirculation; inflammation; endothelium-derived hyperpolarizing factor