Role of EDHF in type 2 diabetes-induced endothelial dysfunction Export

@article{citeulike:3496471, 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 NG-nitro-L-arginine methyl ester (L-NAME, 10 {micro}mol/l) and prostaglandin synthase inhibitor indomethacin (Indo, 10 {micro}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 {micro}mol/l) and apamin (a selective blocker of small-conductance Ca2+-activated K+ channels, 50 {micro}mol/l) also attenuated EDHF-induced vasodilation, but the inhibition of EETs synthesis [14,15-epoxyeicosa-5(Z)-enoic acid; 10 {micro}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 dbTNF-/dbTNF- mice, but neutralizing antibody to IL-6 (anti-IL-6; 0.28 mg{middle dot}ml-1{middle dot}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 dbTNF-/dbTNF- 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. 10.1152/ajpheart.01261.2007}, author = {Park, Yoonjung and Capobianco, Stefano and Gao, Xue and Falck, John R. and Dellsperger, Kevin C. and Zhang, Cuihua}, citeulike-article-id = {3496471}, citeulike-linkout-0 = {http://dx.doi.org/10.1152/ajpheart.01261.2007}, citeulike-linkout-1 = {http://ajpheart.physiology.org/cgi/content/abstract/295/5/H1982}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/18790831}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=18790831}, doi = {10.1152/ajpheart.01261.2007}, journal = {Am J Physiol Heart Circ Physiol}, keywords = {diabetes, edhf, endothelial\_dysfunction, h2o2}, month = {November}, number = {5}, pages = {H1982--1988}, posted-at = {2008-11-08 14:03:33}, priority = {3}, title = {Role of EDHF in type 2 diabetes-induced endothelial dysfunction}, url = {http://dx.doi.org/10.1152/ajpheart.01261.2007}, volume = {295}, year = {2008} }

TY - JOUR ID - citeulike:3496471 L3 - citeulike-article-id:3496471 N2 - 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 NG-nitro-L-arginine methyl ester (L-NAME, 10 {micro}mol/l) and prostaglandin synthase inhibitor indomethacin (Indo, 10 {micro}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 {micro}mol/l) and apamin (a selective blocker of small-conductance Ca2+-activated K+ channels, 50 {micro}mol/l) also attenuated EDHF-induced vasodilation, but the inhibition of EETs synthesis [14,15-epoxyeicosa-5(Z)-enoic acid; 10 {micro}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 dbTNF-/dbTNF- mice, but neutralizing antibody to IL-6 (anti-IL-6; 0.28 mg{middle dot}ml-1{middle dot}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 dbTNF-/dbTNF- 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. 10.1152/ajpheart.01261.2007 IS - 5 JF - Am J Physiol Heart Circ Physiol EP - 1988 TI - Role of EDHF in type 2 diabetes-induced endothelial dysfunction VL - 295 SP - H1982 KW - diabetes KW - edhf KW - endothelial_dysfunction KW - h2o2 AU - Park, Yoonjung AU - Capobianco, Stefano AU - Gao, Xue AU - Falck, John AU - Dellsperger, Kevin AU - Zhang, Cuihua PY - 2008/11/01/ UR - http://dx.doi.org/10.1152/ajpheart.01261.2007 ER -