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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

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