Exercise-induced peptide EIP-22 protect myocardial from ischaemia/reperfusion injury via activating JAK2/STAT3 signalling pathway.
Exercise-induced peptide EIP-22 protect myocardial from ischaemia/reperfusion injury via activating JAK2/STAT3 signalling pathway.
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运动诱导肽EIP-22通过激活JAK2/STAT3信号通路保护心肌免受缺血/再灌注损伤
DOI：
10.1111/jcmm.16441
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发表时间：
2021-04
影响因子：
5.3
通讯作者：
Qian L
中科院分区：
文献类型：
--
作者：
Zhang L;Wang X;Zhang H;Feng M;Ding J;Zhang B;Cheng Z;Qian L
近年来的研究表明，运动具有心肌保护作用，但其确切机制尚不清楚。越来越多的研究发现，肽在心肌缺血再灌注（I/R）损伤中发挥保护作用。然而，关于运动诱导肽在心肌I/R损伤中的作用知之甚少。为了阐明运动诱导肽EIP-22在心肌I/R损伤中的作用，我们首先通过评估细胞活力和乳酸脱氢酶（LDH）水平来确定EIP-22对缺氧/再灌注（H/R）或H2 O2诱导的损伤的作用。荧光显微镜下观察细胞内活性氧（ROS）的积累和线粒体膜电位（MMP）的变化。同时采用Western blot和TUNEL法检测细胞凋亡水平。然后，建立小鼠I/R损伤模型，通过测定心功能、评价心脏病理及检测血清LDH、CK-MB和cTnI水平，验证EIP-22的作用。最后，通过RNA-seq分析主要信号通路。在体外，EIP-22处理显著提高细胞活力和MMP，并减弱LDH、ROS和凋亡水平。在体内，EIP-22可明显改善心功能，改善心肌梗死面积和纤维化，降低血清LDH、CK-MB和cTnI水平。从机制上讲，JAK/STAT信号通路通过RNA-seq聚焦，我们证实EIP-22上调了p-JAK 2和p-STAT 3的表达。此外，JAK 2/STAT 3的选择性抑制剂AG 490消除了EIP-22的保护作用。结果表明，运动诱导肽EIP-22通过激活JAK 2/STAT 3信号通路保护心肌细胞免受心肌I/R损伤，可能成为治疗心肌I/R损伤的新的候选分子。
Recent studies have revealed that exercise has myocardial protective effects, but the exact mechanism remains unclear. Studies have increasingly found that peptides play a protective role in myocardial ischaemia‐reperfusion (I/R) injury. However, little is known about the role of exercise‐induced peptides in myocardial I/R injury. To elucidate the effect of exercise‐induced peptide EIP‐22 in myocardial I/R injury, we first determined the effect of EIP‐22 on hypoxia/reperfusion (H/R)‐ or H2O2‐induced injury via assessing cell viability and lactate dehydrogenase (LDH) level. In addition, reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) was assessed by fluorescence microscope. Meanwhile, Western blot and TUNEL methods were used to detect apoptosis level. Then, we conducted mice I/R injury model and verified the effect of EIP‐22 by measuring cardiac function, evaluating heart pathology and detecting serum LDH, CK‐MB and cTnI level. Finally, the main signalling pathway was analysed by RNA‐seq. In vitro, EIP‐22 treatment significantly improved cells viabilities and MMP and attenuated the LDH, ROS and apoptosis level. In vivo, EIP‐22 distinctly improved cardiac function, ameliorated myocardial infarction area and fibrosis and decreased serum LDH, CK‐MB and cTnI level. Mechanistically, JAK/STAT signalling pathway was focussed by RNA‐seq and we confirmed that EIP‐22 up‐regulated the expression of p‐JAK2 and p‐STAT3. Moreover, AG490, a selective inhibitor of JAK2/STAT3, eliminated the protective roles of EIP‐22. The results uncovered that exercise‐induced peptide EIP‐22 protected cardiomyocytes from myocardial I/R injury via activating JAK2/STAT3 signalling pathway and might be a new candidate molecule for the treatment of myocardial I/R injury.
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