Interleukin-10 protects nitric oxide-dependent relaxation during diabetes: role of superoxide.
Interleukin (IL)-10, an anti-inflammatory cytokine, preserves endothelial function during acute inflammation. We tested the hypotheses that IL-10 plays a protective role in blood vessels during diabetes by suppressing impairment of endothelium-dependent relaxation and that protection by IL-10 is mediated by effects on superoxide (O(2-)). Streptozotocin (150 mg/kg i.p.) or citrate buffer was injected into IL-10-deficient (IL-10(-/-)) mice and wild-type controls (IL-10(+/+)). In IL-10(+/+) and IL-10(-/-) mice, blood glucose levels were approximately 120 mg/dl after citrate administration and approximately 400 mg/dl after streptozotocin administration. Vasorelaxation was examined in arteries in vitro 12-16 weeks later. Maximum relaxation to acetylcholine (30 micromol/l) was 88 +/- 3% (means +/- SE) in nondiabetic mice and 84 +/- 3% in diabetic IL-10(+ /+) mice (P > 0.05). Thus, at this time point, diabetes did not impair endothelium-dependent relaxation in vessels in wild-type mice. In contrast, maximum relaxation in vessels from diabetic IL-10(-/-) mice was significantly decreased (74 +/- 5%) compared with nondiabetic IL-10(-/-) mice (93 +/- 2%, P < 0.05). Superoxide dismutase with polyethylene glycol (PEG-SOD) restored impaired responses to acetylcholine to levels seen in controls. Responses to acetylcholine also were improved by allopurinol (an inhibitor of xanthine oxidase) in vessels from diabetic IL-10(- /-) mice. Thus, diabetes produces greater impairment of relaxation to acetylcholine in IL-10(-/-) mice than in IL-10(+/ +) mice. These findings provide direct evidence that IL-10 impedes mechanisms of endothelial dysfunction during diabetes. Restoration of vasorelaxation with PEG-SOD or allopurinol suggests that the mechanism(s) by which IL-10 preserves endothelium-dependent vasorelaxation involves O(2-), perhaps by reducing production of O(2-) by xanthine oxidase.
Gunnett
Carol A
CA
Department of Internal Medicine, University of Iowa College of Medicine and VA Medical Center, Iowa City, Iowa 52242-1081, USA. carol-gunnett@uiowa.edu
Heistad
Donald D
DD
Faraci
Frank M
FM
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001158:Arteries; D001786:Blood Glucose / Q000032:analysis; D019343:Citric Acid / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005456:Fluorescent Dyes; D016753:Interleukin-10 / Q000172:deficiency / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology; D009569:Nitric Oxide / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D010617:Phenanthridines; D011092:Polyethylene Glycols / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000032:analysis / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000494:pharmacology
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D010617:Phenanthridines; D014662:Vasoconstrictor Agents; D013481:Superoxides; D016753:Interleukin-10; D009599:Nitroprusside; D019343:Citric Acid; D009569:Nitric Oxide; C058428:hydroethidine; D011092:Polyethylene Glycols; D000493:Allopurinol; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D000109:Acetylcholine