Thyroid hormone protects cardiomyocytes from H2O2-induced oxidative stress via the PI3K-AKT signaling pathway.
Thyroid hormone protects cardiomyocytes from H2O2-induced oxidative stress via the PI3K-AKT signaling pathway.
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DOI：
10.1016/j.yexcr.2019.05.003
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发表时间：
2019-07
影响因子：
3.7
通讯作者：
Bin Zeng;Lei Liu;Xiaoting Liao;Caixia Zhang;Huaiyu Ruan
中科院分区：
文献类型：
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作者：
Bin Zeng;Lei Liu;Xiaoting Liao;Caixia Zhang;Huaiyu Ruan
氧化应激在急性心肌梗死、缺血/再灌注（I/R）损伤和心力衰竭等心脏疾病的进展中起重要作用。越来越多的证据表明，甲状腺激素对心血管疾病具有保护作用。然而，关于其对心肌细胞氧化应激的影响或潜在机制知之甚少。本研究表明T3预处理可通过提高左室射血功能和改善I/R损伤引起的病理改变而显著减轻心功能不全。在体外实验中，T3抑制过氧化氢处理的心肌细胞凋亡，表现为Bax表达减少，半胱天冬酶3和9裂解，Bcl-2表达增加。此外，T3预处理可显著减轻I/R损伤小鼠心脏的氧化应激，有效抑制细胞内ROS和线粒体ROS的过度产生，H2 O2处理的离体心肌细胞也可检测到类似的结果。T3显著增加H2 O2处理的心肌细胞中抗氧化蛋白（Nrf 2和HO-1）的表达水平，并抑制NOX 2和NOX 4蛋白的表达水平。此外，T3通过增加线粒体膜电位和促进线粒体生物合成基因的表达来保护线粒体在H2 O2诱导的氧化应激中的功能。值得注意的是，在H2 O2诱导的心肌细胞中，T3预处理显著激活PI 3 K/AKT信号通路。总之，这些研究结果表明，T3可以作为潜在的治疗靶点，通过其抗氧化和抗凋亡作用，这是由PI 3 K/AKT信号通路的激活介导的心脏氧化应激损伤的保护。
Oxidative stress plays an important role in the progression of cardiac diseases, including acute myocardial infarction, ischemia/reperfusion (I/R) injury and heart failure. Growing evidence indicates that thyroid hormone has protective properties against cardiovascular diseases. However, little is known about its effect on oxidative stress in cardiomyocytes or the underlying mechanisms. This study showed that T3 pretreatment in vivo significantly reduced cardiac dysfunction by increasing the left ventricular ejection function and ameliorating the pathological changes induced by I/R-induced injury. In an in vitro experiment, T3 inhibited apoptosis in H2O2-treated cardiomyocytes, as evidenced by the decreased expression of Bax, cleaved caspase 3 and 9, and increased expression of Bcl-2. In addition, oxidative stress observed in hearts of mice with I/R injury was significantly alleviated by T3 pretreatment, intracellular ROS and mitochondrial ROS overproduction were effectively inhibited, and similar results were also detected in H2O2-treated cardiomyocytes in vitro. T3 significantly increased antioxidant protein (Nrf2 and HO-1) expression levels, and inhibited NOX2 and NOX4 protein expression levels in H2O2-treated cardiomyocytes. Moreover, T3 preserved mitochondrial functions upon H2O2-induced oxidative stress by increasing mitochondrial membrane potential and promoting the expression of mitochondrial biogenesis genes. Notably, the PI3K/AKT signaling was significantly activated by T3 pretreatment in H2O2-induced cardiomyocytes. Together, these findings revealed that T3 could be served as potential therapeutic target for protection against cardiac oxidative stress injury through its antioxidant and anti-apoptosis effects, which are mediated by the activation of the PI3K/AKT signaling pathway.