Nutrients · 2025
Silybin Mitigates Post-Myocardial Infarction Heart Failure in Mice via Modulation of HIF-1α-Driven Glycolysis and Energy Metabolism.
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Wang Mengyuan, Chen Jinhong, Zhang Zhongzheng, Wang Tianyu, Zhao Jiaqi, Wang Xiao, Wang Junyan, Zhuang Haowen
Аннотация
BACKGROUND: Post-myocardial infarction (MI) heart failure (HF) is characterized by myocardial energy metabolism disorder, with excessive glycolysis playing a key role in its progression. Silybin (SIL), a flavonoid derived from Silybum marianum, has demonstrated hepatoprotective and metabolic regulatory effects. However, the role of this flavonoid in ameliorating post-myocardial infarction heart failure (post-MI HF) by modulating energy metabolism remains unclear.
METHODS: This study employed an oxygen-glucose deprivation (OGD) model to induce myocardial cell injury in vitro, with YC-1 treatment used to inhibit hypoxia-inducible factor-1α (HIF-1α) for mechanistic validation. A myocardial infarction-induced HF mouse model was used for in vivo experiments.
RESULTS: In vitro, SIL enhanced cell viability, increased ATP levels, and decreased lactate production and reactive oxygen species (ROS) accumulation in OGD-treated myocardial cells. SIL downregulated the mRNA and protein expression of HIF-1α, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), glucose transporter 1 (GLUT1), and lactate dehydrogenase A (LDHA) while inhibiting HIF-1α nuclear translocation. Furthermore, SIL suppressed glycolytic proteins (PFKFB3, GLUT1, and LDHA) in a manner comparable to the HIF-1α inhibitor YC-1. This confirms that SIL's inhibition of glycolysis is HIF-1α-dependent. In vivo, SIL treatment improved cardiac function parameters (LVEF and LVFS) and attenuated left ventricular remodeling (LVID;d and LVID;s) in post-MI HF mice. Additionally, myocardial fibrosis markers were significantly reduced, accompanied by a decrease in the myocardial mRNA and protein expression of glycolytic proteins, including HIF-1α, PFKFB3, GLUT1, and LDHA.
CONCLUSIONS: Silybin effectively ameliorates post-myocardial infarction heart failure through the HIF-1α-mediated regulation of glycolysis, leading to improved myocardial energy metabolism and enhanced cardiac function.
METHODS: This study employed an oxygen-glucose deprivation (OGD) model to induce myocardial cell injury in vitro, with YC-1 treatment used to inhibit hypoxia-inducible factor-1α (HIF-1α) for mechanistic validation. A myocardial infarction-induced HF mouse model was used for in vivo experiments.
RESULTS: In vitro, SIL enhanced cell viability, increased ATP levels, and decreased lactate production and reactive oxygen species (ROS) accumulation in OGD-treated myocardial cells. SIL downregulated the mRNA and protein expression of HIF-1α, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), glucose transporter 1 (GLUT1), and lactate dehydrogenase A (LDHA) while inhibiting HIF-1α nuclear translocation. Furthermore, SIL suppressed glycolytic proteins (PFKFB3, GLUT1, and LDHA) in a manner comparable to the HIF-1α inhibitor YC-1. This confirms that SIL's inhibition of glycolysis is HIF-1α-dependent. In vivo, SIL treatment improved cardiac function parameters (LVEF and LVFS) and attenuated left ventricular remodeling (LVID;d and LVID;s) in post-MI HF mice. Additionally, myocardial fibrosis markers were significantly reduced, accompanied by a decrease in the myocardial mRNA and protein expression of glycolytic proteins, including HIF-1α, PFKFB3, GLUT1, and LDHA.
CONCLUSIONS: Silybin effectively ameliorates post-myocardial infarction heart failure through the HIF-1α-mediated regulation of glycolysis, leading to improved myocardial energy metabolism and enhanced cardiac function.