Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen, China.
Eur J Pharmacol. 2023 Oct 15;957:176044. doi: 10.1016/j.ejphar.2023.176044. Epub 2023 Sep 1.
Ginsenoside Rd, one of the main active components in ginseng, exerts various biological activities. However, its effectiveness on myocardial ischemia injury and its potential mechanism need further clarification. The model of isoproterenol (ISO)-induced myocardial ischemia injury (MI) mice and cobalt chloride (CoCl)-induced cardiomyocytes injury were performed. Ginsenoside Rd significantly alleviated MI injury, as evidenced by ameliorated cardiac pathological features and improved cardiac function. Simultaneously, ginsenoside Rd notably mitigated CoCl-induced cell injury, decreased the lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) generation in vitro. Additionally, ginsenoside Rd increased nicotinamide adenine dinucleotide (NADH) and mitochondrial membrane potential (MMP). Moreover, we found that ginsenoside Rd could increase the mitochondrial DNA (mtDNA) and promote the expression of Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1α), nuclear factor erythroid 2 related factor-1 (NRF1), nuclear factor erythroid 2 related factor-2 (NRF2) and activating mitochondrial transcription factor A (TFAM), which suggested that ginsenoside Rd might accelerate mitochondrial biogenesis function to ameliorate MI injury. Importantly, ginsenoside Rd treatment significantly inhibited the WNT5A/calcium (Ca) signaling pathway, decreased the expression of WNT5A, Frizzled2, phosphorylated calmodulin kinase II/calmodulin kinase II (p-CaMKII/CaMKII) and the calcium overload. Meanwhile, WNT5A siRNA was further conducted to elucidate the effect of ginsenoside Rd on CoCl-induced cardiomyocyte injury. And we found that WNT5A siRNA partially weakened the protective effects of ginsenoside Rd on mitochondrial function and mitochondrial biogenesis, suggesting that ginsenoside Rd might suppress myocardial ischemia injury through WNT5A. Overall, this study demonstrated that ginsenoside Rd could alleviate myocardial ischemia injury through improving mitochondrial biogenesis via WNT5A/Ca pathways, which provided a rationale for future clinical applications and potential drugs for the treatment of cardiovascular diseases.
人参中的主要活性成分之一人参皂苷 Rd 具有多种生物学活性。然而，其在心肌缺血损伤中的有效性及其潜在机制仍需进一步阐明。本研究采用异丙肾上腺素（ISO）诱导的心肌缺血损伤（MI）小鼠模型和氯化钴（CoCl）诱导的心肌细胞损伤模型进行实验。实验结果表明，人参皂苷 Rd 显著减轻了 MI 损伤，改善了心脏病理特征，改善了心脏功能。同时，人参皂苷 Rd 显著减轻了 CoCl 诱导的细胞损伤，降低了体外乳酸脱氢酶（LDH）释放和活性氧（ROS）生成。此外，人参皂苷 Rd 增加了烟酰胺腺嘌呤二核苷酸（NADH）和线粒体膜电位（MMP）。此外，我们发现人参皂苷 Rd 可以增加线粒体 DNA（mtDNA）并促进过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC1α）、核因子红细胞 2 相关因子 1（NRF1）、核因子红细胞 2 相关因子 2（NRF2）和激活线粒体转录因子 A（TFAM）的表达，这表明人参皂苷 Rd 可能通过加速线粒体生物发生功能来改善 MI 损伤。重要的是，人参皂苷 Rd 处理显著抑制了 WNT5A/钙（Ca）信号通路，降低了 WNT5A、Frizzled2、磷酸化钙调蛋白激酶 II/钙调蛋白激酶 II（p-CaMKII/CaMKII）和钙超载的表达。同时，进一步进行了 WNT5A siRNA 实验以阐明人参皂苷 Rd 对 CoCl 诱导的心肌细胞损伤的影响。我们发现 WNT5A siRNA 部分减弱了人参皂苷 Rd 对线粒体功能和线粒体生物发生的保护作用，表明人参皂苷 Rd 可能通过 WNT5A 抑制心肌缺血损伤。总的来说，这项研究表明，人参皂苷 Rd 通过 WNT5A/Ca 通路改善线粒体生物发生来减轻心肌缺血损伤，为未来心血管疾病的临床应用和潜在药物提供了依据。
