Role of EDHF in type 2 diabetes-induced endothelial dysfunction.
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 N(G)-nitro-L-arginine methyl ester (L-NAME, 10 micromol/l) and prostaglandin synthase inhibitor indomethacin (Indo, 10 mumol/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 micromol/l) and apamin (a selective blocker of small-conductance Ca2+-activated K+ channels, 50 micromol/l) also attenuated EDHF-induced vasodilation, but the inhibition of EETs synthesis [14,15-epoxyeicosa-5(Z)-enoic acid; 10 mumol/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 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.
Park
Yoonjung
Y
Department of Internal Medicine, Medical Pharmacology and Physiology and Nutritional Science, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO 65211, USA.
Capobianco
Stefano
S
Gao
Xue
X
Falck
John R
JR
Dellsperger
Kevin C
KC
Zhang
Cuihua
C
D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000503:physiopathology; D001685:Biological Factors / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003331:Coronary Vessels / Q000378:metabolism / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D001685:Biological Factors; D001786:Blood Glucose; D016861:Cyclooxygenase Inhibitors; D015850:Interleukin-6; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase
Am J Physiol. 1994 May;266(5 Pt 2):H2061-7
7515589
J Mol Cell Cardiol. 2005 Nov;39(5):725-32
16122755
FASEB J. 1989 Jul;3(9):2007-18
2545495
Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):2035-42
16794224
Circ Res. 2006 Jul 7;99(1):69-77
16741160
J Mol Cell Cardiol. 1999 Jan;31(1):15-22
10072712
Br J Pharmacol. 2006 Jun;148(4):434-41
16682967
Br J Pharmacol. 1997 Aug;121(7):1383-91
9257918
Cardiovasc Res. 2007 Oct 1;76(1):81-90
17612514
Am J Physiol Regul Integr Comp Physiol. 2006 Mar;290(3):R546-52
16467502
Nature. 1998 Nov 19;396(6708):269-72
9834033
Diabetes. 2003 Nov;52(11):2784-9
14578297
Circ Res. 2003 Feb 21;92(3):322-9
12595345
Endocrinology. 2005 Aug;146(8):3417-27
15845623
Br J Pharmacol. 2005 Feb;144(4):477-85
15655533
Am J Physiol Heart Circ Physiol. 2001 Jul;281(1):H232-40
11406490
News Physiol Sci. 2000 Feb;15:1-5
11390867
J Cardiovasc Pharmacol. 1996 Nov;28(5):703-11
8945685
Rev Endocr Metab Disord. 2004 Aug;5(3):189-97
15211090
Circ Res. 1999 Mar 5;84(4):484-8
10066684
Eur J Pharmacol. 2006 Dec 3;551(1-3):98-107
17027963
Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2614-21
17023676
Circ Res. 2002 May 17;90(9):1028-36
12016270
Br J Pharmacol. 2002 Mar;135(5):1133-43
11877319
Circulation. 2003 Feb 25;107(7):1040-5
12600919
Arterioscler Thromb Vasc Biol. 2006 Mar;26(3):475-80
16385082
Nature. 1980 Nov 27;288(5789):373-6
6253831
Br J Pharmacol. 2000 Jun;130(3):549-56
10821782
Br J Pharmacol. 2002 Dec;137(8):1346-54
12466245
Biochem Biophys Res Commun. 2003 Dec 26;312(4):1202-8
14652001
Circulation. 2007 Jan 16;115(2):245-54
17200442
Methods. 2001 Dec;25(4):402-8
11846609
Arterioscler Thromb Vasc Biol. 2006 Jun;26(6):1215-25
16543495
Diabetes. 2003 Jul;52(7):1799-805
12829649
Clin Exp Pharmacol Physiol. 2005 May-Jun;32(5-6):482-7
15854163
Arterioscler Thromb Vasc Biol. 2003 Jul 1;23(7):1224-30
12763764
Cardiovasc Res. 1999 Jul;43(1):200-9
10536705
Pharmacol Rev. 1978 Sep;30(3):293-331
116251
Br J Pharmacol. 2000 Jul;130(5):963-74
10882379
JAMA. 2001 Jul 18;286(3):327-34
11466099
Circulation. 1999 Jun 22;99(24):3132-8
10377076