Kanglexin delays heart aging by promoting mitophagy
Kanglexin delays heart aging by promoting mitophagy
复制标题
康乐欣通过促进线粒体自噬延缓心脏衰老
DOI：
10.1038/s41401-021-00686-5
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发表时间：
2021-05-25
影响因子：
8.2
通讯作者：
Yang, Bao-feng
中科院分区：
文献类型：
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作者：
Li, Hui-min;Liu, Xin;Yang, Bao-feng
心脏老化的特征是心脏结构和舒张功能障碍。然而，目前还没有有效的药物来预防和治疗衰老引起的心功能异常变化。本文介绍了大黄素及其衍生物康乐新（KLX）对心脏衰老的预防作用。我们发现，KLX和大黄素可以明显减轻d -半乳糖（D-gal）诱导衰老小鼠的舒张功能障碍和心脏重构。此外，KLX和大黄素也能逆转D-gal诱导的新生小鼠心肌细胞衰老。而在相同剂量下，KLX的抗心脏衰老作用优于大黄素。在衰老的心脏和衰老的新生小鼠心肌细胞中观察到线粒体自噬失调，KLX比大黄素更能增加线粒体自噬。KLX和大黄素促进线粒体自噬的作用主要是由于它们能不同程度地增强线粒体自噬的关键调节因子Parkin的蛋白稳定性。分子对接和SPR分析表明，与大黄素相比，KLX对Parkin的泛素样（UBL）结构域具有更高的亲和力。UBL结构域可能参与了KLX对Parkin的稳定作用。总之，本研究确定了KLX和大黄素是有效的抗心脏衰老药物，可以激活帕金森介导的有丝分裂，并概述了它们可能的治疗重要性。
Heart aging is characterized by structural and diastolic dysfunction of the heart. However, there is still no effective drug to prevent and treat the abnormal changes in cardiac function caused by aging. Here, we present the preventive effects of emodin and its derivative Kanglexin (KLX) against heart aging. We found that the diastolic dysfunction and cardiac remodeling in mice with D-galactose (D-gal)-induced aging were markedly mitigated by KLX and emodin. In addition, the senescence of neonatal mouse cardiomyocytes induced by D-gal was also reversed by KLX and emodin treatment. However, KLX exhibited better anti-heart aging effects than emodin at the same dose. Dysregulated mitophagy was observed in aging hearts and in senescent neonatal mouse cardiomyocytes, and KLX produced a greater increase in mitophagy than emodin. The mitophagy-promoting effects of KLX and emodin were ascribed to their abilities to enhance the protein stability of Parkin, a key modulator in mitophagy, with different potencies. Molecular docking and SPR analysis demonstrated that KLX has a higher affinity for the ubiquitin-like (UBL) domain of Parkin than emodin. The UBL domain might contribute to the stabilizing effects of KLX on Parkin. In conclusion, this study identifies KLX and emodin as effective anti-heart aging drugs that activate Parkin-mediated mitophagy and outlines their putative therapeutic importance.