Recently, attention has been drawn to the adverse outcomes of N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6PPDQ) on human health, but its cardiac toxicity has been relatively understudied. This work aims to investigate the effects of 6PPDQ on differentiated H9c2 cardiomyocytes. Our findings demonstrated that exposure to 6PPDQ altered cellular morphology and disrupted the expression of cardiac-specific markers. Significantly, 6PPDQ exposure led to cardiomyocyte senescence, characterized by elevated β-Galactosidase activity, upregulation of cell cycle inhibitor, induction of DNA double-strand breaks, and remodeling of Lamin B1. Furthermore, 6PPDQ hindered autophagy flux by promoting the formation of autophagosomes while inhibiting the degradation of autolysosomes. Remarkably, restoration of autophagic flux using rapamycin counteracted 6PPDQ-induced cardiomyocyte senescence. Additionally, our study revealed that 6PPDQ significantly increased the ROS production. However, ROS scavenger effectively reduced the blockage of autophagic flux and cardiomyocyte senescence caused by 6PPDQ. Furthermore, we discovered that 6PPDQ activated the Aryl hydrocarbon receptor (AhR) signaling pathway. AhR antagonist was found to reverse the blockage of autophagy and alleviate cardiac senescence, while also reducing ROS levels in 6PPDQ-treated group. In conclusion, our research unveils that exposure to 6PPDQ induces ROS overproduction through AhR activation, leading to disruption of autophagy flux and ultimately contributing to cardiomyocyte senescence.

中文翻译：

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6PPDQ 通过 AhR/ROS 介导的自噬通量阻断诱导心肌细胞衰老

近年来，N-(1,3-二甲基丁基)-N'-苯基对苯二胺醌(6PPDQ)对人类健康的不良后果引起了人们的关注，但其心脏毒性的研究相对较少。本工作旨在研究6PPDQ对分化的H9c2心肌细胞的影响。我们的研究结果表明，暴露于 6PPDQ 会改变细胞形态并扰乱心脏特异性标志物的表达。值得注意的是，暴露于 6PPDQ 会导致心肌细胞衰老，其特征是 β-半乳糖苷酶活性升高、细胞周期抑制剂上调、诱导 DNA 双链断裂以及核纤层蛋白 B1 重塑。此外，6PPDQ 通过促进自噬体的形成同时抑制自噬溶酶体的降解来阻碍自噬通量。值得注意的是，使用雷帕霉素恢复自噬流可以抵消 6PPDQ 诱导的心肌细胞衰老。此外，我们的研究表明 6PPDQ 显着增加了 ROS 的产生。然而，ROS清除剂有效减少了6PPDQ引起的自噬流阻断和心肌细胞衰老。此外，我们发现 6PPDQ 激活芳基碳氢化合物受体 (AhR) 信号通路。在 6PPDQ 治疗组中，AhR 拮抗剂被发现可以逆转自噬的阻断并减轻心脏衰老，同时还降低 ROS 水平。总之，我们的研究表明，暴露于 6PPDQ 会通过 AhR 激活诱导 ROS 过量产生，导致自噬流破坏，最终导致心肌细胞衰老。