Liu Kuang, Zhu Yihao, Gao Wenjie, Han Xuhui, Zhang Qinghua, Zhao Yanbin, Zu Yao
International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; Marine Biomedical Science and Technology Innovation Platform of Lin-gang Special Area, Shanghai 201306, China.
International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
Biomed Pharmacother. 2024 Dec;181:117716. doi: 10.1016/j.biopha.2024.117716. Epub 2024 Dec 2.
Resveratrol has been extensively studied for its multifaceted health benefits. Nonetheless, the pharmacological mechanisms of resveratrol for heart failure remain elusive, especially the cardioprotective effects. To address this knowledge gap, we performed high-throughput drug screening using zebrafish and discovered that resveratrol significantly alleviated heart failure, including rescuing abnormalities in heart rate, blood flow, cardiac output, and nppb overexpression. Mechanically, calcium optical mapping revealed that resveratrol diminished the prolongation of calcium duration at 90 % repolarization (CaD90). Membrane potential assay demonstrated that resveratrol alleviated mitochondrial damage, subsequently relieved the excessive accumulation of reactive oxygen species (ROS). Tunel staining further showed that resveratrol inhibited cardiomyocyte apoptosis both in zebrafish and human AC16 cell. Given the close relationship between the Forkhead Box O (foxo) family and oxidative stress and apoptosis, we used qPCR and noted that resveratrol could regulate the heart failure-induced expressions of foxo1b and foxo3a to normal levels. Furthermore, we conducted in situ hybridization to confirm the effective down-regulation patterns of foxo3a after resveratrol treatment. To investigate whether resveratrol's effects are mediated via foxo3a, we used gardenoside to inhibit foxo3a expression, noting that resveratrol's cardioprotective effects were reduced with foxo3a inhibition. Overall, our study underscores the molecular mechanisms by which resveratrol confers cardioprotection and provides a reference for heart failure therapeutic approaches.
白藜芦醇因其多方面的健康益处而受到广泛研究。尽管如此，白藜芦醇治疗心力衰竭的药理机制仍不清楚，尤其是其心脏保护作用。为了填补这一知识空白，我们利用斑马鱼进行了高通量药物筛选，发现白藜芦醇能显著缓解心力衰竭，包括挽救心率、血流、心输出量异常以及nppb过表达。从机制上讲，钙光学映射显示白藜芦醇减少了90%复极化时钙持续时间（CaD90）的延长。膜电位测定表明白藜芦醇减轻了线粒体损伤，随后缓解了活性氧（ROS）的过度积累。Tunel染色进一步显示白藜芦醇在斑马鱼和人AC16细胞中均抑制心肌细胞凋亡。鉴于叉头框O（foxo）家族与氧化应激和凋亡之间的密切关系，我们使用qPCR并注意到白藜芦醇可将心力衰竭诱导的foxo1b和foxo3a表达调节至正常水平。此外，我们进行了原位杂交以确认白藜芦醇处理后foxo3a的有效下调模式。为了研究白藜芦醇的作用是否通过foxo3a介导，我们使用栀子苷抑制foxo3a表达，注意到随着foxo3a的抑制，白藜芦醇的心脏保护作用降低。总体而言，我们的研究强调了白藜芦醇赋予心脏保护作用的分子机制，并为心力衰竭治疗方法提供了参考。
