Role of EDHF in type 2 diabetes-induced endothelial dysfunction
Role of EDHF in type 2 diabetes-induced endothelial dysfunction
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DOI：
10.1152/ajpheart.01261.2007
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发表时间：
2008-11-01
影响因子：
4.8
通讯作者：
Zhang, Cuihua
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文献类型：
--
作者：
Park, Yoonjung;Capobianco, Stefano;Zhang, Cuihua
杨文，李文. EDHF在2型糖尿病诱导的内皮功能障碍中的作用Am J Physiol Heart Circ Physiol 295：H1982-H1988，2008.首次发表于2008年9月12日; doi：10.1152/ajpheart.01261.2007。- 内皮源性超极化因子（Endothelium-derived hyperpolarizing factor，EDHF）在调节血管紧张性中起着重要作用，尤其是在糖尿病等一氧化氮依赖性控制受损的微血管中。环氧二十碳三烯酸（EHF）、钾离子（K+）和过氧化氢（H2 O2）被认为是EDHF。然而，EDHF依赖性内皮扩张剂的特性（或特性）在糖尿病中尚未明确阐明。我们在野生型（WT，正常）、db/db（晚期2型糖尿病）小鼠和TNF无效的db/db小鼠（db（TNF-）/db（TNF-））中评估了EDHF诱导的血管舒张机制。在db/db小鼠中，EDHF诱导的血管舒张[在N-G-硝基-L-精氨酸甲酯存在下ACh诱导的血管舒张（L-NAME，10 μ mol/l）和前列腺素合成酶抑制剂吲哚美辛（Indo，10 μ mol/l）]在给予过氧化氢酶后减少（将H2 O2选择性歧化为水和氧的酶，1，000 U/ml）;施用卡律巴毒素和卡律巴毒素的组合（一种非选择性的中电导Ca 2+激活的K+通道阻滞剂，10 μ mol/l）和蜂毒肽（小电导Ca 2+激活K+通道的选择性阻断剂，50 μ mol/l）也减弱EDHF诱导的血管舒张作用，但抑制雌二醇合成[14，15-epoxyeicosa-5（Z）- enoic acid; 10 μ mol/l]不改变EDHF诱导的血管舒张。在WT对照组中，在抑制K+通道、E2合成或H2 O2产生后，EDHF依赖性血管舒张显著减少。我们的分子结果表明，与WT和db（TNF-）/db（TNF-）小鼠相比，db/db小鼠中白细胞介素-6（IL-6）的mRNA和蛋白表达更高，但IL-6的中和抗体（抗IL-6; 0.28 mg . ml（-1）。kg（-1）ip 3天）减弱db/db小鼠中IL-6的表达。在WT小鼠中，在L-NAME和Indo存在下，用IL-6（5 ng/ml）孵育微血管诱导内皮功能障碍，但在db/db小鼠中，在L-NAME和Indo存在下，抗IL-6恢复了ACh诱导的血管舒张。在db（TNF-）/db（TNF-）小鼠中，EDHF诱导的血管舒张更大，与对照组相当，但IL-6降低EDHF介导的血管舒张。我们的研究结果表明，EDHF补偿减少NO依赖性扩张IL-6诱导内皮功能障碍的激活H2 O2或K+通道在2型糖尿病。
Park Y, Capobianco S, Gao X, Falck JR, Dellsperger KC, Zhang C. Role of EDHF in type 2 diabetes-induced endothelial dysfunction. Am J Physiol Heart Circ Physiol 295: H1982-H1988, 2008. First published September 12, 2008; doi:10.1152/ajpheart.01261.2007. - 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 mu mol/l) and prostaglandin synthase inhibitor indomethacin (Indo, 10 mu mol/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 mu mol/l) and apamin (a selective blocker of small-conductance Ca2+-activated K+ channels, 50 mu mol/l) also attenuated EDHF-induced vasodilation, but the inhibition of EETs synthesis [14,15-epoxyeicosa-5(Z)- enoic acid; 10 mu mol/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.