Zhou Ziwei, Song Zhimin, Guo Xiaomeng, Wang Qi, Li Meijing, Zhang Minyu, Gong Muxin
School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China.
Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing 100069, China.
Pharmaceuticals (Basel). 2025 Mar 30;18(4):500. doi: 10.3390/ph18040500.
Heart failure (HF), the terminal stage of cardiovascular disease with high morbidity and mortality, remains poorly managed by current therapies. Ventricular remodeling in HF is fundamentally characterized by myocardial fibrosis. While ginsenoside Rb has demonstrated anti-fibrotic effects in HF, the underlying mechanism remains unclear. Twist1, an upstream regulator of energy metabolism factors PGC-1α and PPARα, may attenuate fibrosis by preserving systemic energy homeostasis, suggesting its pivotal role in HF pathogenesis. This study explores ginsenoside Rb's anti-HF mechanisms through the regulation of ginsenoside Rb on these metabolic regulators. Sprague Dawley rats were subjected to a ligation of the left anterior descending coronary artery to induce an HF model, followed by ginsenoside Rb treatment for 6 weeks. Therapeutic effects were evaluated through cardiac function assessment, myocardial histopathological staining (HE, Masson, immunofluorescence, immunohistochemistry), mitochondrial morphology observation (transmission electron microscopy), energy metabolism analysis (electron transport chain efficiency, mitochondrial membrane potential, ATP content), and protein expression profiling (Twist1, PGC-1α, PPARα, GLUT4, PPARγ). Additionally, H9c2 cells induced with endothelin-1 to model HF were employed as an in vitro model to further investigate ginsenoside Rb's regulatory effects on the Twist1/PGC-1α/PPARα signaling pathway. Ginsenoside Rb can restore cardiac function in HF rats, improve mitochondrial function, alleviate energy metabolism disorders, and inhibit ventricular remodeling. By modulating the Twist1/PGC-1α/PPARα signaling pathway, ginsenoside Rb suppressed the abnormal overexpression of Twist1 and maintained normal expression of downstream PGC-1α and PPARα. In vitro experiments further demonstrated that ginsenoside Rb significantly inhibited Twist1 expression in H9c2 cardiomyocytes with HF while promoting PGC-1α and PPARα expression, thereby restoring myocardial energy metabolism and mitigating ventricular remodeling in HF. Ginsenoside Rb can inhibit the upregulation of Twist1 and activate the expression of its downstream PGC-1α and PPARα expression, by modulating the Twist1/PGC-1α/PPARα signaling pathway, alleviating ventricular remodeling in HF patients and improving myocardial energy metabolism dysfunction. Twist1 may be a key target for the treatment of HF. This study not only elucidates the mechanism by which ginsenoside Rb alleviates HF, but also provides new insights into the clinical treatment of HF.
心力衰竭（HF）是心血管疾病的终末期，发病率和死亡率高，目前的治疗方法对其管理效果不佳。HF中的心室重塑基本特征是心肌纤维化。虽然人参皂苷Rb已在HF中显示出抗纤维化作用，但其潜在机制仍不清楚。Twist1是能量代谢因子PGC-1α和PPARα的上游调节因子，可能通过维持全身能量稳态来减轻纤维化，表明其在HF发病机制中起关键作用。本研究通过人参皂苷Rb对这些代谢调节因子的调控来探索其抗HF机制。将Sprague Dawley大鼠进行左冠状动脉前降支结扎以诱导HF模型，随后用人参皂苷Rb治疗6周。通过心脏功能评估、心肌组织病理学染色（苏木精-伊红、Masson、免疫荧光、免疫组织化学）、线粒体形态观察（透射电子显微镜）、能量代谢分析（电子传递链效率、线粒体膜电位、ATP含量）和蛋白质表达谱分析（Twist1、PGC-1α、PPARα、GLUT4、PPARγ）来评估治疗效果。此外，以内皮素-1诱导的H9c2细胞作为HF的体外模型，进一步研究人参皂苷Rb对Twist1/PGC-1α/PPARα信号通路的调节作用。人参皂苷Rb可恢复HF大鼠的心脏功能，改善线粒体功能，减轻能量代谢紊乱，并抑制心室重塑。通过调节Twist1/PGC-1α/PPARα信号通路，人参皂苷Rb抑制Twist1的异常过表达，并维持下游PGC-1α和PPARα的正常表达。体外实验进一步证明，人参皂苷Rb可显著抑制HF的H9c2心肌细胞中Twist1的表达，同时促进PGC-1α和PPARα的表达，从而恢复心肌能量代谢并减轻HF中的心室重塑。人参皂苷Rb可通过调节Twist1/PGC-1α/PPARα信号通路抑制Twist1的上调并激活其下游PGC-1α和PPARα的表达，减轻HF患者的心室重塑并改善心肌能量代谢功能障碍。Twist1可能是治疗HF的关键靶点。本研究不仅阐明了人参皂苷Rb减轻HF的机制，还为HF的临床治疗提供了新的见解。
