Laboratory of Biochemistry, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-8012, USA.
Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1513-8. doi: 10.1152/ajpheart.00441.2011. Epub 2011 Aug 12.
Methionine sulfoxide reductase A (MsrA) catalytically scavenges reactive oxygen species and also repairs oxidized methionines in proteins. Increasing MsrA protects cells and organs from a variety of oxidative stresses while decreasing MsrA enhances damage, but the mechanisms of action have not been elucidated. A single gene encodes MsrA of which ∼25% is targeted to the mitochondria, a major site of reactive oxygen species production. The other ∼75% is targeted to the cytosol and is posttranslationally modified by myristoylation. To determine the relative importance of MsrA in each compartment in protecting against ischemia-reperfusion damage, we created a series of transgenic mice overexpressing MsrA targeted to the mitochondria or the cytosol. We used a Langendorff model of ischemia-reperfusion and assayed both the rate pressure product and infarct size following ischemia and reperfusion as measures of injury. While the mitochondrially targeted MsrA was expected to be protective, it was not. Notably, the cytosolic form was protective but only if myristoylated. The nonmyristoylated, cytosolic form offered no protection against injury. We conclude that cytosolic MsrA protects the heart from ischemia-reperfusion damage. The requirement for myristoylation suggests that MsrA must interact with a hydrophobic domain to provide protection.
甲硫氨酸亚砜还原酶 A（MsrA）可催化清除活性氧物种，并修复蛋白质中的氧化甲硫氨酸。增加 MsrA 可以保护细胞和器官免受各种氧化应激，而减少 MsrA 则会增强损伤，但作用机制尚未阐明。一个基因编码 MsrA，其中约 25%靶向线粒体，线粒体是活性氧产生的主要部位。其余约 75%靶向细胞质，并通过豆蔻酰化进行翻译后修饰。为了确定 MsrA 在每个隔室中对抗缺血再灌注损伤的相对重要性，我们创建了一系列过表达靶向线粒体或细胞质的 MsrA 的转基因小鼠。我们使用 Langendorff 缺血再灌注模型，在缺血和再灌注后测定心率压力产物和梗死面积，作为损伤的衡量标准。虽然预期靶向线粒体的 MsrA 具有保护作用，但实际上并非如此。值得注意的是，细胞质形式具有保护作用，但前提是豆蔻酰化。非豆蔻酰化的细胞质形式对损伤没有保护作用。我们得出结论，细胞质 MsrA 可保护心脏免受缺血再灌注损伤。豆蔻酰化的要求表明，MsrA 必须与疏水区相互作用才能提供保护。
