Mitochondrial dysfunction and endoplasmic reticulum (ER) stress contribute to postischemic myocardial damage, but the upstream regulatory mechanisms have not been identified. In this study, we analyzed the role of mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) in the regulation of mitochondrial function and ER stress in hypoxic cardiomyocytes. Our results show that MKP-1 overexpression sustains viability and reduces hypoxia-induced apoptosis among H9C2 cardiomyocytes. MKP-1 overexpression attenuates ER stress and expression of ER stress genes and improves mitochondrial function in hypoxia-treated H9C2 cells. MKP-1 overexpression also increases ATP production and mitochondrial respiration and attenuates mitochondrial oxidative damage in hypoxic cardiomyocytes. Moreover, our results demonstrate that ERK and JNK are the downstream signaling targets of MKP-1 and that MKP-1 overexpression activates ERK, while it inhibits JNK. Inhibition of ERK reduces the ability of MKP-1 to preserve mitochondrial function and ER homeostasis in hypoxic cardiomyocytes. These results show that MKP-1 plays an essential role in the regulation of mitochondrial function and ER stress in hypoxic H9C2 cardiomyocytes through normalization of the ERK pathway and suggest that MKP-1 may serve as a novel target for the treatment of postischemic myocardial injury.

中文翻译：

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MKP-1 过表达通过减轻 ER 应激和线粒体损伤来减少缺血后心肌损伤

线粒体功能障碍和内质网（ER）应激导致缺血后心肌损伤，但上游调节机制尚未确定。在本研究中，我们分析了丝裂原激活蛋白激酶 (MAPK) 磷酸酶 1 (MKP-1) 在调节缺氧心肌细胞线粒体功能和 ER 应激中的作用。我们的结果表明，MKP-1 过表达可维持 H9C2 心肌细胞的活力并减少缺氧诱导的细胞凋亡。MKP-1 过表达可减弱 ER 应激和 ER 应激基因的表达，并改善缺氧处理的 H9C2 细胞中的线粒体功能。MKP-1 过表达还会增加 ATP 产生和线粒体呼吸，并减轻缺氧心肌细胞中的线粒体氧化损伤。此外，我们的结果表明，ERK 和 JNK 是 MKP-1 的下游信号传导靶点，并且 MKP-1 过表达会激活 ERK，同时抑制 JNK。抑制 ERK 会降低 MKP-1 在缺氧心肌细胞中保护线粒体功能和 ER 稳态的能力。这些结果表明，MKP-1通过ERK通路的正常化，在缺氧H9C2心肌细胞线粒体功能和ER应激的调节中发挥重要作用，并表明MKP-1可能作为治疗缺血后心肌损伤的新靶点。