Role of EDHF in type 2 diabetes-induced endothelial dysfunction

Yoonjung Park, Stefano Capobianco, Xue Gao, John R. Falck, Kevin C Dellsperger, Cuihua Zhang

Research output: Contribution to journalArticle

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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 (H 2O2) 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 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 Ca 2+-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 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 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume295
Issue number5
DOIs
StatePublished - Nov 1 2008

Fingerprint

Type 2 Diabetes Mellitus
Endothelium
Vasodilation
Interleukin-6
NG-Nitroarginine Methyl Ester
Microvessels
Charybdotoxin
Apamin
Calcium-Activated Potassium Channels
Cyclooxygenase Inhibitors
Interleukin-5
Neutralizing Antibodies
Indomethacin
Catalase
Hydrogen Peroxide
Dilatation
Potassium
Nitric Oxide
Ions
Oxygen

Keywords

  • Acetylcholine
  • Coronary Disease
  • Endothelium
  • Endothelium-derived hyperpolarizing factor
  • Inflammation
  • Microcirculation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Role of EDHF in type 2 diabetes-induced endothelial dysfunction. / Park, Yoonjung; Capobianco, Stefano; Gao, Xue; Falck, John R.; Dellsperger, Kevin C; Zhang, Cuihua.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 295, No. 5, 01.11.2008.

Research output: Contribution to journalArticle

Park, Yoonjung ; Capobianco, Stefano ; Gao, Xue ; Falck, John R. ; Dellsperger, Kevin C ; Zhang, Cuihua. / Role of EDHF in type 2 diabetes-induced endothelial dysfunction. In: American Journal of Physiology - Heart and Circulatory Physiology. 2008 ; Vol. 295, No. 5.
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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 (H 2O2) 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 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 Ca 2+-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 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 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.

AB - 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 (H 2O2) 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 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 Ca 2+-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 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 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.

KW - Acetylcholine

KW - Coronary Disease

KW - Endothelium

KW - Endothelium-derived hyperpolarizing factor

KW - Inflammation

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