Senior Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, China.
Department of Cardiology, The First Medical Center of People's Liberation Army General Hospital, China.
Oxid Med Cell Longev. 2021 Sep 2;2021:8905578. doi: 10.1155/2021/8905578. eCollection 2021.
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.
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。在这项研究中，我们分析了丝裂原活化蛋白激酶（MAPK）磷酸酶 1（MKP-1）在调节低氧心肌细胞中线粒体功能和 ER 应激中的作用。我们的结果表明，MKP-1 的过表达可维持 H9C2 心肌细胞的活力并减少低氧诱导的细胞凋亡。MKP-1 的过表达可减轻 ER 应激和 ER 应激基因的表达，并改善低氧处理的 H9C2 细胞中的线粒体功能。MKP-1 的过表达还增加了 ATP 的产生和线粒体呼吸，并减轻了低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 的下游信号靶标，并且 MKP-1 的过表达激活了 ERK，同时抑制了 JNK。ERK 的抑制降低了 MKP-1 在低氧心肌细胞中维持线粒体功能和 ER 平衡的能力。这些结果表明，MKP-1 通过正常化 ERK 途径在调节低氧 H9C2 心肌细胞中线粒体功能和 ER 应激中发挥重要作用，并表明 MKP-1 可能成为治疗缺血后心肌损伤的新靶点。
