Institute for Experimental Surgery, University of Rostock, Schillingallee 69a, Rostock, Germany.
Exp Gerontol. 2011 Nov;46(11):868-76. doi: 10.1016/j.exger.2011.07.008. Epub 2011 Jul 27.
The objective of this study is to clarify whether age-related oxidative stress enhances hepatic vulnerability via increased interaction of advanced glycation endproducts (AGE) with their receptor RAGE. To further address the role of uncoupling of mitochondrial respiration, mitochondrial uncoupling protein-2 wild-type (UCP2+/+) and knock out (UCP2-/-) mice were used and studied at an age of 8 (young), 38 (adult) and 76 weeks (senescent). First, we could show that UCP2 protein expression increased with age in UCP2+/+ mice. Second, in both mouse strains oxidative stress, as measured by malondialdehyde concentrations and the ratio of glutathione to glutathione disulfide, as well as hepatic RAGE expression and highly modified AGE accumulation significantly increased with age. This, however, was far more pronounced in UCP2-/- mice, in particular at the young age of 8 wk. In addition, the hepatic activity of the AGE precursor detoxifying enzyme glyoxalase-I was significantly decreased in 8 wk old UCP2-/- animals and concomitantly caused 2-fold higher levels of methylglyoxal-modified AGE in these animals. We further showed that the numbers of hepatic cells expressing sRAGE which acts as a decoy for RAGE ligands decreased with age and were markedly lower in the UCP2-/- than the UCP2+/+ mice. As a consequence, young 8 wk old UCP2-/- mice benefited from treatment with recombinant mouse RAGE to block the RAGE/AGE interaction, when challenged with galactosamine/lipopolysaccharide for the induction of acute liver injury. They showed less pronounced tissue damage and slightly lower mortality rate, while older UCP2+/+ and UCP2-/- mice revealed comparably high mortality rates and extent of liver injury, irrespective of their treatment with rRAGE. Taken together, the present study underlines the role of UCP2 in the age-related increase of oxidative stress and the oxidative stress-related RAGE/AGE interaction. In young animals, blockade of the RAGE/AGE interaction is of benefit, while in older animals, this protective effect is lost, supposedly due to the fact that with age other factors than enhanced hepatic glycation products predominantly determine liver injury and injury-related mortality rate.
本研究旨在阐明年龄相关性氧化应激是否通过增加晚期糖基化终产物（AGE）与其受体 RAGE 的相互作用来增强肝脏易损性。为了进一步探讨线粒体呼吸解偶联的作用，使用了线粒体解偶联蛋白 2 野生型（UCP2+/+）和敲除（UCP2-/-）小鼠，并在 8 周（年轻）、38 周（成年）和 76 周（衰老）时进行了研究。首先，我们可以证明 UCP2 蛋白表达随着 UCP2+/+ 小鼠年龄的增长而增加。其次，在两种小鼠品系中，氧化应激（通过丙二醛浓度和谷胱甘肽与谷胱甘肽二硫化物的比值来衡量）以及肝 RAGE 表达和高度修饰的 AGE 积累均随着年龄的增长而显著增加。然而，在 UCP2-/- 小鼠中，这种情况更为明显，尤其是在 8 周龄的年轻时期。此外，AGE 前体解毒酶甘油醛酶-I 的肝活性在 8 周龄 UCP2-/- 动物中显著降低，同时导致这些动物中甲基乙二醛修饰的 AGE 水平增加 2 倍。我们还表明，表达 sRAGE 的肝细胞数量随着年龄的增长而减少，并且在 UCP2-/- 小鼠中明显低于 UCP2+/+ 小鼠。因此，年轻的 8 周龄 UCP2-/- 小鼠在接受重组鼠 RAGE 治疗以阻断 RAGE/AGE 相互作用后，在接受半乳糖胺/脂多糖诱导急性肝损伤时受益。它们显示出较轻的组织损伤和较低的死亡率，而年龄较大的 UCP2+/+ 和 UCP2-/- 小鼠则显示出相似的高死亡率和肝损伤程度，而不管它们是否接受 rRAGE 治疗。总之，本研究强调了 UCP2 在年龄相关性氧化应激增加和氧化应激相关 RAGE/AGE 相互作用中的作用。在年轻动物中，阻断 RAGE/AGE 相互作用是有益的，而在老年动物中，这种保护作用丧失，这可能是因为随着年龄的增长，除了增强的肝糖基化产物外，其他因素主要决定了肝损伤和损伤相关的死亡率。
