Thioredoxin protects mitochondrial structure, function and biogenesis in myocardial ischemia-reperfusion via redox-dependent activation of AKT-CREB- PGC1α pathway in aged mice.
Thioredoxin protects mitochondrial structure, function and biogenesis in myocardial ischemia-reperfusion via redox-dependent activation of AKT-CREB- PGC1α pathway in aged mice.
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硫氧还蛋白通过氧化还原依赖性激活AKT-CREB-PGC 1 α通路保护老龄小鼠心肌缺血再灌注时线粒体结构、功能和生物合成
DOI：
10.18632/aging.104071
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发表时间：
2020-10-13
期刊：
影响因子：
--
通讯作者：
Das KC
中科院分区：
文献类型：
--
作者：
Subramani J;Kundumani-Sridharan V;Das KC
衰老是心血管疾病的独立危险因素，例如由于心脏的缺血再灌注损伤（I/R）引起的心肌梗死。胞浆硫氧还蛋白（Trx）是一种多功能氧化还原蛋白，具有抗氧化和蛋白质二硫键还原特性。我们假设，高水平的Trx将防止多因素疾病，如心肌梗死由于I/R损伤老年小鼠。对过表达人Trx（Trx-Tg）的老龄小鼠、表达人Trx氧化还原失活突变体（dnTrx-Tg）的小鼠和非转基因同窝小鼠（NT）进行I/R（60/30 min），评价这些小鼠的心脏功能、线粒体结构和功能以及PGC 1 α通路的生物发生。虽然老年Trx-Tg小鼠免受I/R诱导的射血分数（EF）和缩短分数（FS）的降低，具有较小的梗死伴细胞凋亡减少和线粒体功能保留，但老年dnTrx-Tg小鼠表现出增强的心肌损伤和线粒体功能障碍。此外，Trx-Tg小鼠可免受I/R诱导的心肌中PGC 1 α、ACO 2、MFN 1和MFN 2的损失。dnTrx-Tg小鼠对I/R诱导的细胞凋亡高度敏感。总之，我们的研究表明，老龄NT或dnTrx-Tg小鼠I/R中Trx氧化还原平衡的丧失导致PGC 1 α表达降低，从而降低线粒体基因表达，增加心肌细胞凋亡。高水平的Trx而非线粒体硫氧还蛋白（Trx-2）维持了I/R中Trx的氧化还原平衡，导致PGC 1 α表达增加，通过AKT/CREB激活上调线粒体基因表达和保护免受I/R损伤。
Aging is an independent risk factor for cardiovascular diseases, such as myocardial infarction due to ischemia-reperfusion injury (I/R) of the heart. Cytosolic thioredoxin (Trx) is a multifunctional redox protein which has antioxidant and protein disulfide reducing properties. We hypothesized that high levels of Trx will protect against multifactorial disease such as myocardial infarction due to I/R injury in aged mice. Aged mice overexpressing human Trx (Trx-Tg), mice expressing redox-inactive mutant of human Trx (dnTrx-Tg) and non-transgenic litter-mates (NT) were subjected to I/R (60/30 min), and cardiac function, mitochondrial structure and function, and biogenesis involving PGC1α pathway were evaluated in these mice. While aged Trx-Tg mice were protected from I/R-induced reduction in ejection fraction (EF) and fractional shortening (FS), had smaller infarct with decreased apoptosis and preserved mitochondrial function, aged dnTrx-Tg mice showed enhanced myocardial injury and mitochondrial dysfunction. Further, Trx-Tg mice were protected from I/R induced loss of PGC1α, ACO2, MFN1 and MFN2 in the myocardium. The dnTrx-Tg mice were highly sensitive to I/R induced apoptosis. Overall, our study demonstrated that the loss of Trx redox balance in I/R in aged NT or dnTrx-Tg mice resulted in decreased PGC1α expression that decreased mitochondrial gene expression with increased myocardial apoptosis. High levels of Trx, but not mitochondrial thioredoxin (Trx-2) maintained Trx redox balance in I/R resulting in increased PGC1α expression via AKT/CREB activation upregulating mitochondrial gene expression and protection against I/R injury.
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DOI：
10.1152/ajpheart.00836.2009
发表时间：
2009-12
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
--
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2003-02-18
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10.1152/ajplung.00285.2014
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2015-03-01
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4.9
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