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, 211198, China.
Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
Redox Biol. 2023 Apr;60:102610. doi: 10.1016/j.redox.2023.102610. Epub 2023 Jan 14.
Ginsenoside Rd is an active ingredient in Panax ginseng CA Mey and can be absorbed into the adipose tissue. Adipokines play an important role in the treatment of cardiovascular diseases. However, the potential benefit of Rd on heart failure (HF) and the underlying mechanism associated with the crosstalk between adipocytes and cardiomyocytes remains to be illustrated. Here, the results identified that Rd improved cardiac function and inhibited cardiac pathological changes in transverse aortic constriction (TAC), coronary ligation (CAL) and isoproterenol (ISO)-induced HF mice. And Rd promoted the release of omentin from the adipose tissue and up-regulated omentin expression in lipopolysaccharide (LPS)-induced 3T3-L1 adipocytes. Further, Rd could increase TBK1 and AMPK phosphorylation in adipocytes. And also, the TBK1-AMPK signaling pathway regulated the expression of omentin in LPS-induced adipocytes. Moreover, the omentin mRNA expression was significantly decreased by TBK1 knockdown in LPS-induced 3T3-L1 adipocytes. Additionally, molecular docking and SPR analysis confirmed that Rd had a certain binding ability with TBK1, and co-treatment with TBK1 inhibitors or TBK1 knockdown partially abolished the effect of Rd on increasing the omentin expression and the ratio of p-AMPK to AMPK in adipocytes. Moreover, we found that circulating omentin level diminished in the HF patients compared with healthy subjects. Meanwhile, the adipose tissue-specific overexpression of omentin improved cardiac function, reduced myocardial infarct size and ameliorated cardiac pathological features in CAL-induced HF mice. Consistently, exogenous omentin reduced mtROS levels and restored ΔψM to improve oxygen and glucose deprivation (OGD)-induced cardiomyocytes injury. Further, omentin inhibited the WNT5A/Ca signaling pathway and promoted mitochondrial biogenesis function to ameliorate myocardial ischemia injury. However, WNT5A knockdown inhibited the impairment of mitochondrial biogenesis and partially counteracted the cardioprotective effect of omentin in vitro. Therefore, this study indicated that Rd promoted omentin secretion from adipocytes through the TBK1-AMPK pathway to improve mitochondrial biogenesis function via WNT5A/Ca signaling pathway to ameliorate myocardial ischemia injury, which provided a new therapeutic mechanism and potential drugs for the treatment of HF.
人参皂苷 Rd 是人参中的一种活性成分，可被吸收到脂肪组织中。脂肪因子在心血管疾病的治疗中起着重要作用。然而，Rd 在心衰（HF）中的潜在益处以及脂肪细胞和心肌细胞之间相互作用的潜在机制仍有待阐明。在这里，研究结果表明，Rd 改善了横主动脉缩窄（TAC）、冠状动脉结扎（CAL）和异丙肾上腺素（ISO）诱导的 HF 小鼠的心脏功能并抑制了心脏病理变化。并且 Rd 促进了脂肪组织中网膜素的释放，并上调了脂多糖（LPS）诱导的 3T3-L1 脂肪细胞中网膜素的表达。此外，Rd 可增加脂肪细胞中 TBK1 和 AMPK 的磷酸化。并且，TBK1-AMPK 信号通路调节 LPS 诱导的脂肪细胞中网膜素的表达。此外，LPS 诱导的 3T3-L1 脂肪细胞中 TBK1 敲低显著降低了网膜素 mRNA 的表达。此外，分子对接和 SPR 分析证实 Rd 与人 TBK1 具有一定的结合能力，并且 TBK1 抑制剂或 TBK1 敲低的共同处理部分消除了 Rd 对增加脂肪细胞中网膜素表达和 p-AMPK/AMPK 比值的作用。此外，我们发现 HF 患者的循环网膜素水平较健康受试者降低。同时，脂肪组织特异性过表达网膜素可改善心脏功能，减少心肌梗死面积，并改善 CAL 诱导的 HF 小鼠的心脏病理特征。一致地，外源性网膜素可降低 mtROS 水平并恢复ΔψM，从而改善 OGD 诱导的心肌细胞损伤。此外，网膜素抑制 WNT5A/Ca 信号通路并促进线粒体生物发生功能以改善心肌缺血损伤。然而，WNT5A 敲低抑制了线粒体生物发生的损害，并在体外部分抵消了网膜素的心脏保护作用。因此，这项研究表明，Rd 通过 TBK1-AMPK 途径促进脂肪细胞中网膜素的分泌，通过 WNT5A/Ca 信号通路改善线粒体生物发生功能，从而改善心肌缺血损伤，为 HF 的治疗提供了新的治疗机制和潜在药物。
