Medizinische Klinik und Poliklinik I, Munich Heart Alliance, Klinikum Grosshadern of the Ludwig Maximilians-University, Munich, Germany.
Circulation. 2011 Dec 20;124(25):2892-902. doi: 10.1161/CIRCULATIONAHA.111.059253. Epub 2011 Dec 5.
Excessive formation of reactive oxygen species contributes to tissue injury and functional deterioration after myocardial ischemia/reperfusion. Especially, mitochondrial reactive oxygen species are capable of opening the mitochondrial permeability transition pore, a harmful event in cardiac ischemia/reperfusion. Thioredoxins are key players in the cardiac defense against oxidative stress. Mutations in the mitochondrial thioredoxin reductase (thioredoxin reductase-2, Txnrd2) gene have been recently identified to cause dilated cardiomyopathy in patients. Here, we investigated whether mitochondrial thioredoxin reductase is protective against myocardial ischemia/reperfusion injury.
In mice, α-MHC-restricted Cre-mediated Txnrd2 deficiency, induced by tamoxifen (Txnrd2-/-ic), aggravated systolic dysfunction and cardiomyocyte cell death after ischemia (90 minutes) and reperfusion (24 hours). Txnrd2-/-ic was accompanied by a loss of mitochondrial integrity and function, which was resolved on pretreatment with the reactive oxygen species scavenger N-acetylcysteine and the mitochondrial permeability transition pore blocker cyclosporin A. Likewise, Txnrd2 deletion in embryonic endothelial precursor cells and embryonic stem cell-derived cardiomyocytes, as well as introduction of Txnrd2-shRNA into adult HL-1 cardiomyocytes, increased cell death on hypoxia and reoxygenation, unless N-acetylcysteine was coadministered.
We report that Txnrd2 exerts a crucial function during postischemic reperfusion via thiol regeneration. The efficacy of cyclosporin A in cardiac Txnrd2 deficiency may indicate a role for Txnrd2 in reducing mitochondrial reactive oxygen species, thereby preventing opening of the mitochondrial permeability transition pore.
活性氧的过度形成导致心肌缺血/再灌注后的组织损伤和功能恶化。特别是线粒体活性氧能够打开线粒体通透性转换孔，这是心肌缺血/再灌注中的一种有害事件。硫氧还蛋白是心脏对抗氧化应激的关键因素。最近发现，线粒体硫氧还蛋白还原酶（硫氧还蛋白还原酶-2，Txnrd2）基因的突变可导致患者扩张型心肌病。在这里，我们研究了线粒体硫氧还蛋白还原酶是否对心肌缺血/再灌注损伤具有保护作用。
在小鼠中，α-MHC 限制的 Cre 介导的 Txnrd2 基因缺失（通过他莫昔芬诱导，Txnrd2-/-ic）加重了缺血（90 分钟）和再灌注（24 小时）后的收缩功能障碍和心肌细胞死亡。Txnrd2-/-ic 伴随着线粒体完整性和功能的丧失，这在使用活性氧清除剂 N-乙酰半胱氨酸和线粒体通透性转换孔阻滞剂环孢菌素 A 预处理后得到解决。同样，胚胎内皮前体细胞和胚胎干细胞衍生的心肌细胞中的 Txnrd2 缺失，以及成年 HL-1 心肌细胞中 Txnrd2-shRNA 的引入，增加了缺氧和再氧合后的细胞死亡，除非同时给予 N-乙酰半胱氨酸。
我们报告称，Txnrd2 通过硫醇再生在缺血后再灌注期间发挥关键作用。环孢菌素 A 在心脏 Txnrd2 缺乏中的疗效可能表明 Txnrd2 在减少线粒体活性氧方面的作用，从而防止线粒体通透性转换孔的打开。
