Aging-Dependent Reduction in Glyoxalase 1 Delays Wound Healing
Aging-Dependent Reduction in Glyoxalase 1 Delays Wound Healing
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DOI：
10.1159/000351628
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发表时间：
2013-01-01
期刊：
影响因子：
3.5
通讯作者：
Nawroth, Peter P.
中科院分区：
文献类型：
--
作者：
Fleming, Thomas H.;Theilen, Till-Martin;Nawroth, Peter P.
乙二醛(MG)是乙二醛酶1(GLO1)的主要二羰基底物，是通过糖酵解助熔剂形成的反应性代谢产物。研究表明，GLO1活性的降低会导致MG的积聚和晚期糖基化终产物的增加，这两种产物在生理性衰老过程中都会积累，在糖尿病和其他慢性退行性疾病中会加速积累。为了确定MG水平升高导致的生理后果以及MG和GLO1在衰老中的作用，对幼年(=52周)野生型小鼠的伤口愈合进行了研究。与年轻小鼠相比，老年小鼠的伤口愈合率显著降低(6d时74.9%+/-2.2vs.55.4%+/-1.5%；减少26%；p<；0.0001)。这与GLO1转录、表达和活性降低有关。通过对GLO1的抑制，证实了GLO1在小鼠体内的重要性。将MG直接应用于幼鼠创面，与未处理的小鼠相比，创面愈合率降低24%，而应用经MG修饰的BSA则没有影响。用游离MG的清除剂氨基胍处理幼鼠和老龄小鼠，第6天伤口闭合率分别增加16%(66.8±1.6vs.77.2±3.1%；p<；0.05)和%(40.4±7.9vs.66.4±5.2%；p<；0.05)。这些发现在体外得到了证实，因为MG减少了来自年轻和老年野生型小鼠的成纤维细胞的迁移和增殖。这些数据表明，MG和年龄依赖的GLO1下调之间的平衡导致了老年小鼠伤口愈合的延迟。版权所有(C)2013 S.Karger AG，巴塞尔
Methylglyoxal (MG), the major dicarbonyl substrate of the enzyme glyoxalase 1 (GLO1), is a reactive metabolite formed via glycolytic flux. Decreased GLO1 activity in situ has been shown to result in an accumulation of MG and increased formation of advanced glycation endproducts, both of which can accumulate during physiological aging and at an accelerated rate in diabetes and other chronic degenerative diseases. To determine the physiological consequences which result from elevated MG levels and the role of MG and GLO1 in aging, wound healing in young (= 52 weeks) wild-type mice was studied. Old mice were found to have a significantly slower rate of wound healing compared to young mice (74.9 +/- 2.2 vs. 55.4 +/- 1.5% wound closure at day 6; 26% decrease; p < 0.0001). This was associated with decreases in GLO1 transcription, expression and activity. The importance of GLO1 was confirmed in mice by inhibition of GLO1. Direct application of MG to the wounds of young mice, decreased wound healing by 24% compared to untreated mice, whereas application of BSA modified minimally by MG had no effect. Treatment of either young or old mice with aminoguanidine, a scavenger of free MG, significantly increased wound closure by 16% (66.8 +/- 1.6 vs. 77.2 +/- 3.1%; p < 0.05) and 64% (40.4 +/- 7.9 vs. 66.4 +/- 5.2%; p < 0.05), respectively, by day 6. As a result of the aminoguanidine treatment, the overall rate of wound healing in the old mice was restored to the level observed in the young mice. These findings were confirmed in vitro, as MG reduced migration and proliferation of fibroblasts derived from young and old, wild-type mice. The data demonstrate that the balance between MG and age-dependent GLO1 downregulation contributes to delayed wound healing in old mice. Copyright (C) 2013 S. Karger AG, Basel