Ginsenoside Rd attenuates myocardial ischemia injury through improving mitochondrial biogenesis via WNT5A/Ca2+ pathways.
Ginsenoside Rd attenuates myocardial ischemia injury through improving mitochondrial biogenesis via WNT5A/Ca2+ pathways.
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DOI：
10.1016/j.ejphar.2023.176044
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发表时间：
2023-09
影响因子：
5
通讯作者：
Zekun Cui;Li-fei Gu;Tao Liu;Yining Liu;Boyang Yu;J. Kou;Fang Li;Kun Yang
中科院分区：
文献类型：
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作者：
Zekun Cui;Li-fei Gu;Tao Liu;Yining Liu;Boyang Yu;J. Kou;Fang Li;Kun Yang
人参皂苷Rd是人参的主要活性成分之一，具有多种生物活性。然而，其对心肌缺血损伤的疗效及其可能的机制尚需进一步阐明。建立异丙肾上腺素(ISO)诱导的小鼠心肌缺血损伤(MI)模型和氯化钴(CoCl2)诱导的心肌细胞损伤模型。人参皂苷RD可明显减轻心肌梗死损伤，改善心脏病理特征，改善心功能。同时，人参皂苷RD可明显减轻CoCl2诱导的细胞损伤，减少乳酸脱氢酶(LDH)的释放，减少细胞内ROS的产生。此外，人参皂苷Rd还能增加烟酰胺腺嘌呤二核苷酸(NADH)和线粒体膜电位(MMP)。此外，我们还发现人参皂苷RD能增加线粒体DNA，促进过氧化物酶体增殖物激活受体-1α(Pg1-α)、核因子-红系2相关因子-1、核因子-红系2相关因子-2和激活线粒体转录因子A的表达，提示人参皂苷-D可能促进线粒体生物发生功能，从而改善心肌梗死损伤。重要的是，人参皂苷RD处理显著抑制Wnt5A/钙(Ca~(2+))信号通路，降低Wnt5A、Frizzled2、磷酸化钙调蛋白激酶II/钙调蛋白激酶II(p-CaMKII/CaMKII)的表达和钙超载。同时，用Wnt5A siRNA进一步阐明人参皂苷Rd对CoCl2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，提示人参皂苷Rd可能通过Wnt5A抑制心肌缺血损伤。综上所述，本研究证实人参皂苷RD通过Wnt5A/Ca~(2+)途径促进线粒体生物发生，从而减轻心肌缺血损伤，为今后临床应用和治疗心血管疾病的潜在药物提供了理论依据。
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 (CoCl2)-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 CoCl2-induced cell injury, decreased the lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) generationin 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 (Ca2+) 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 CoCl2-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/Ca2+pathways, which provided a rationale for future clinical applications and potential drugs for the treatment of cardiovascular diseases.