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HydroMg通过减轻氧化应激与改善线粒体功能缓解阿霉素慢性心脏毒性

HydroMg alleviates doxorubicin-induced chronic cardiotoxicity by attenuating oxidative stress and improving mitochondrial function

    摘要
  • 摘要:
    目的 探讨新型缓释氢供体HydroMg对阿霉素诱导慢性心脏毒性模型的缓解作用及机制。
    方法 给予H9C2细胞阿霉素（1 μmol/L）和（或） HydroMg （1 μg/mL），检测线粒体膜电位、活性氧水平及细胞凋亡情况。将小鼠分为对照组、HydroMg干预组、阿霉素干预组和HydroMg联合阿霉素干预组（联合干预组）。HydroMg干预组腹腔注射HydroMg 100 mg/kg；阿霉素干预组和HydroMg联合阿霉素干预组连续4周腹腔注射阿霉素（每周5 mg/kg），其中联合干预组在每次阿霉素注射前4～5 h腹腔注射HydroMg 100 mg/kg。通过心脏超声、心脏重量指数评估HydroMg对小鼠心功能、心脏重构的影响，并分析小鼠生存情况。对阿霉素干预组小鼠的心脏组织进行转录组测序，分析与对照组的关键分子差异。
    结果 在细胞层面，HydroMg处理有效逆转了阿霉素诱导的线粒体功能障碍与氧化应激，表现为膜电位恢复，ROS及线粒体超氧化物水平分别降低约30%和9%，细胞凋亡率从34.13%降至18.27%。在动物模型中，与阿霉素干预组相比，联合干预组左心室射血分数（left ventricular ejection fraction, LVEF）、左心室短轴缩短率（left ventricular fractional shortening, LVFS）分别提高9.62%、5.82%，心脏重量指数下降减轻（4.41 mg/mm vs 3.53 mg/mm），4周生存率提高（80% vs 60%）。转录组分析表明，阿霉素心脏毒性的核心分子特征包括氧化磷酸化及抗氧化通路广泛抑制。
    结论 HydroMg通过减轻氧化应激和改善线粒体功能，缓解阿霉素诱导的慢性心脏损伤，为防治阿霉素心肌损伤提供了潜在治疗方法。

     

    Abstract:
    Objective To investigate the protective effect and underlying mechanisms of HydroMg, a novel sustained-release hydrogen donor, in a model of doxorubicin (DOX)-induced chronic cardiotoxicity.
    Methods H9C2 cells were treated with 1 μmol/L DOX and/or 1 μg/mL HydroMg, and mitochondrial membrane potential, reactive oxygen species (ROS) levels, and apoptosis were measured. In the animal experiment, mice were divided into control, HydroMg, DOX, and DOX＋HydroMg groups. The HydroMg group received intraperitoneal injection of HydroMg (100 mg/kg). Chronic cardiotoxicity was established by intraperitoneal injection of DOX (5 mg/kg every week) for four consecutive weeks; In the DOX＋HydroMg group, HydroMg (100 mg/kg) was administered intraperitoneally 4–5 h prior to each DOX injection. Cardiac function and remodeling were evaluated by echocardiography and heart weight index (HWI). The long-term survival of mice were analyzed. Subsequently, transcriptome sequencing was performed on myocardial tissues from the DOX group to identify key molecular alterations compared with controls.
    Results At the cellular level, HydroMg treatment effectively reversed DOX-induced mitochondrial dysfunction and oxidative stress, as evidenced by restored membrane potential, reductions in total ROS and mitochondrial superoxide levels by approximately 30% and 9%, respectively, and a decrease in the apoptosis rate from 34.13% to 18.27%. In the animal model, compared with the DOX group, HydroMg intervention increased left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) by 9.62% and 5.82%, respectively, attenuated the reduction in HWI (4.41 mg/mm vs 3.53 mg/mm), and improved the 4-week survival rate (80% vs 60%). Transcriptomic analysis revealed that the core molecular features of DOX-induced cardiotoxicity, including widespread suppression of oxidative phosphorylation and antioxidant pathways.
    Conclusions HydroMg protects against DOX-induced chronic cardiotoxicity by alleviating oxidative stress and improving mitochondrial function, and provides a potential therapeutic strategy against DOX-related cardiotoxicity.

     

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