Metallothionein prevents cardiac pathological changes in diabetes by modulating nitration and inactivation of cardiac ATP synthase
Metallothionein prevents cardiac pathological changes in diabetes by modulating nitration and inactivation of cardiac ATP synthase
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金属硫蛋白通过调节心脏 ATP 合成酶的硝化和失活来预防糖尿病的心脏病理变化
DOI：
10.1016/j.jnutbio.2013.12.007
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发表时间：
2014-04-01
影响因子：
5.6
通讯作者：
Cai, Lu
中科院分区：
文献类型：
--
作者：
Cong, Weitao;Zhao, Ting;Cai, Lu
线粒体ATP的产生是细胞的主要能量来源。糖尿病降低了ATP的有效生成，可能是由于ATP合成酶的失活。然而，糖尿病诱导ATP合酶失活的确切机制尚不清楚，以及这种失活是否在糖尿病心脏病理异常的发展中起作用。为了解决这些问题，我们使用了心脏金属硫蛋白转基因（MT-TG）和野生型（WT）小鼠与链脲霉素诱导的糖尿病，因为我们之前已经证明糖尿病诱导的心脏损伤和重塑在WT糖尿病小鼠中发现，而在MT-TG糖尿病小鼠中没有发现。采用免疫组织化学和生化方法比较MT-TG和WT糖尿病小鼠的心脏病理和生化变化，并采用蛋白质组学方法评估ATP合成酶的表达和酪氨酸硝化及其活性。LC/MS分析显示，糖尿病增加了Tyr（271）、Tyr（311）和Tyr（426）上ATP合成酶a亚基的酪氨酸硝化，以及Tyr（269）和Tyr（508）上β亚基的酪氨酸硝化，并显著降低了ATP合成酶活性，降低率约为32%。这些变化在MT-TG糖尿病小鼠中未观察到。此外，通过补充锌诱导糖尿病小鼠心脏MT表达的平行实验也产生了类似的效果。这些结果表明，MT可能通过抑制ATP合成酶硝化作用来维持链脲佐菌素诱导的糖尿病中ATP合成酶的活性。(C) 2014爱思唯尔公司版权所有。
Mitochondrial ATP production is the main energy source for the cell. Diabetes reduces the efficient generation of ATP, possibly due to the inactivation of ATP synthase. However, the exact mechanism by which diabetes induces inactivation of ATP synthase remains unknown, as well as whether such inactivation has a role in the development of pathological abnormalities of the diabetic heart. To address these issues, we used cardiac metallothionein-transgenic (MT-TG) and wild-type (WT) mice with streptozotocin-induced diabetes, since we have demonstrated previously that diabetes-induced cardiac damage and remodeling were found in WT diabetic mice, but not in MT-TG diabetic mice. Immunohistochemical and biochemical assays were used to compare pathological and biochemical changes of the heart between MT-TG and WT diabetic mice, and a proteomic assay to evaluate ATP synthase expression and tyrosine nitration, with its activity. LC/MS analysis revealed that diabetes increased tyrosine nitration of the ATP synthase a subunit at Tyr(271), Tyr(311), and Tyr(426), and the beta subunit at Tyr(269) and Tyr(508), and also significantly reduced ATP synthase activity by similar to 32%. These changes were not observed in MT-TG diabetic mice. Furthermore, parallel experiments with induced expression of cardiac MT by zinc supplementation in diabetic mice produced similar effects. These results suggest that MT can preserve ATP synthase activity in streptozotocin-induced diabetes, probably through the inhibition of ATP synthase nitration. (C) 2014 Elsevier Inc. All rights reserved.