Interleukin-10 protects nitric oxide-dependent relaxation during diabetes - Role of superoxide
Interleukin-10 protects nitric oxide-dependent relaxation during diabetes - Role of superoxide
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DOI：
10.2337/diabetes.51.6.1931
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发表时间：
2002-06-01
期刊：
影响因子：
7.7
通讯作者：
Faraci, FM
中科院分区：
文献类型：
--
作者：
Gunnett, CA;Heistad, DD;Faraci, FM
白细胞介素（IL）-10，一种抗炎细胞因子，在急性炎症期间保护内皮功能。我们检验了以下假设：IL-10通过抑制内皮依赖性舒张功能受损在糖尿病期间对血管起保护作用，IL-10的保护作用是通过对超氧化物（O-2（-））的影响介导的。链脲霉素（150 mg/kg i. p.）或柠檬酸盐缓冲液注射到IL-10缺陷（IL-10（-/-））小鼠和野生型对照（IL-10（+/+））中。在IL-10（+/+）和IL-10（-/-）小鼠中，柠檬酸盐给药后血糖水平与120 mg/dl相似，链脲佐菌素给药后血糖水平与400 mg/dl相似。12-16周后在离体动脉中检查血管舒张。非糖尿病小鼠对乙酰胆碱（30 mumol/l）的最大松弛度为88 +/- 3%（平均SE），糖尿病IL-10（+/+）小鼠为843%（P > 0.05）。因此，在这个时间点，糖尿病不会损害野生型小鼠血管中的内皮依赖性舒张。相比之下，糖尿病IL-10（-/-）小鼠的血管最大舒张显著低于非糖尿病IL-10（-/-）小鼠（74 +/- 5%）（93 +/-2%，P < 0.05）。超氧化物歧化酶与聚乙二醇（PEG-SOD）恢复受损的乙酰胆碱的水平在控制。别嘌呤醇（黄嘌呤氧化酶抑制剂）也可以改善糖尿病IL-10（-/-）小鼠血管中对乙酰胆碱的反应。因此，糖尿病在IL-10（-/-）小鼠中产生比在IL-10（+/+）小鼠中更大的对乙酰胆碱的松弛的损害。这些发现为IL-10阻碍糖尿病期间内皮功能障碍的机制提供了直接证据。用PEG-SOD或别嘌呤醇恢复血管舒张表明IL-10维持内皮依赖性血管舒张的机制涉及O-2（-），可能是通过减少黄嘌呤氧化酶产生O-2（-）。
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 similar to120 mg/dl after citrate administration and similar to400 mg/dl after streptozotocin administration. Vasorelaxation was examined in arteries in vitro 12-16 weeks later. Maximum relaxation to acetylcholine (30 mumol/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.