Purpose

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among one of the most commonly prescribed medications for pain and inflammation. Diclofenac (DIC) is a commonly prescribed NSAID that is known to increase the risk of cardiovascular diseases. However, the mechanisms underlying its cardiotoxic effects remain largely unknown. In this study, we tested the hypothesis that chronic exposure to DIC increases oxidative stress, which ultimately impairs cardiovascular function.

Methods and Results

Mice were treated with DIC for 4 weeks and subsequently subjected to in vivo and in vitro functional assessments. Chronic DIC exposure resulted in not only systolic but also diastolic dysfunction. DIC treatment, however, did not alter blood pressure or electrocardiographic recordings. Importantly, treatment with DIC significantly increased inflammatory cytokines and chemokines as well as cardiac fibroblast activation and proliferation. There was increased reactive oxygen species (ROS) production in cardiomyocytes from DIC-treated mice, which may contribute to the more depolarized mitochondrial membrane potential and reduced energy production, leading to a significant decrease in sarcoplasmic reticulum (SR) Ca²⁺ load, Ca²⁺ transients, and sarcomere shortening. Using unbiased metabolomic analyses, we demonstrated significant alterations in oxylipin profiles towards inflammatory features in chronic DIC treatment.

Conclusions

Together, chronic treatment with DIC resulted in severe cardiotoxicity, which was mediated, in part, by an increase in mitochondrial oxidative stress.

中文翻译：

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慢性双氯芬酸暴露会增加线粒体氧化应激、炎症介质和心脏功能障碍

目的

非甾体类抗炎药 (NSAID) 是最常用于治疗疼痛和炎症的处方药之一。双氯芬酸 (DIC) 是一种常用的非甾体抗炎药，已知会增加患心血管疾病的风险。然而，其心脏毒性作用的潜在机制在很大程度上仍然未知。在这项研究中，我们检验了长期暴露于 DIC 会增加氧化应激，最终损害心血管功能的假设。

方法和结果

小鼠用 DIC 治疗 4 周，随后进行体内和体外功能评估。慢性 DIC 暴露不仅会导致收缩功能障碍，还会导致舒张功能障碍。然而，DIC 治疗并未改变血压或心电图记录。重要的是，DIC 治疗显着增加了炎症细胞因子和趋化因子以及心脏成纤维细胞的活化和增殖。DIC 处理小鼠的心肌细胞中活性氧 (ROS) 的产生增加，这可能导致线粒体膜电位去极化和能量产生减少，从而导致肌浆网 (SR) Ca 2+ 负荷显着降低^， Ca ²⁺瞬变和肌节缩短。使用无偏代谢组学分析，我们证明了慢性 DIC 治疗中 oxylipin 谱对炎症特征的显着改变。

结论

总之，慢性 DIC 治疗导致严重的心脏毒性，这在一定程度上是由线粒体氧化应激的增加介导的。