Ginseng polysaccharides reduce myocardial ischemia-reperfusion injury via suppressing ferroptosis

Background and Purpose: Myocardial ischemia-reperfusion injury (MIRI) is a major contributor to global morbidity and mortality, necessitating novel therapeutic strategies. WGPA, polysaccharides fraction derived from Panax ginseng C.A. Meyer, exhibits diverse pharmacological properties. This study aimed to elucidate the cardioprotective mechanisms of WGPA against MIRI through ferroptosis inhibition in vivo and in vitro, thereby establishing a foundation for precise MIRI treatment.

Methods & Results: An in vitro MIRI model was established using H9c2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R). WGPA treatment (50, 100, and 200 μg/mL) significantly enhanced cell viability and reduced creatine kinase (CK) and lactate dehydrogenase (LDH) release in H/R-injured cardiomyocytes. Furthermore, WGPA alleviated oxidative stress by suppressing reactive oxygen species (ROS) and malondialdehyde (MDA) production while augmenting superoxide dismutase (SOD) activity. WGPA also decreased intracellular ferrous (Fe²?) and ferric (Fe³?) iron levels, inhibited lipid peroxidation, and attenuated lipid ROS accumulation. Transmission electron microscopy (TEM) revealed that H/R-induced ferroptosis-related mitochondrial damage—characterized by diminished cristae and ruptured outer membranes—was mitigated by WGPA, which preserved mitochondrial ultrastructure. Mitochondrial membrane potential (MMP) assays confirmed WGPA’s ability to counteract H/R-induced MMP dissipation. Mechanistically, WGPA elevated glutathione (GSH and GSSG) levels, upregulated ferroptosis-suppressing proteins (FTH1, GPX4, HO-1, and Nrf2), and downregulated the pro-ferroptotic protein ACSL4. In C57BL/6J mice, an isoproterenol (ISO)-induced MIRI model was employed. Pre-treatment with WGPA (50, 100, and 200 mg/kg, oral) for 7 days, followed by concurrent ISO injection (40 mg/kg, subcutaneous) for 3 days, significantly reduced infarct size and serum LDH/CK levels. Histopathological analysis via hematoxylin-eosin (HE) staining demonstrated that WGPA attenuated ISO-induced myocardial abnormalities, including fiber disarray, edema, and inflammatory infiltration, while alleviating ST-segment elevation. WGPA also suppressed myocardial lipid peroxidation (reduced MDA, elevated SOD) and modulated ferroptosis-related protein expression (upregulated FTH1, GPX4, HO-1, Nrf2; downregulated ACSL4). Notably, co-administration of the ferroptosis inducer erastin reversed WGPA’s cardioprotective effects in both models. In a permanent left anterior descending coronary artery (LAD) ligation-induced myocardial infarction model in SD rats, echocardiography revealed that WGPA administration significantly preserved cardiac function, attenuated myocardial enzyme elevation, mitigated oxidative stress, and maintained cardiomyocyte structural integrity. Notably, the ferroptosis inducer erastin abolished WGPA-mediated cardioprotection both in vitro and in vivo, validating its mechanism of action via ferroptosis inhibition.

Conclusion: The underlying mechanisms of WGPA’s therapeutic potential for MIRI involve oxidative stress mitigation, mitochondrial functional preservation, and regulation of ferroptosis pathways, underscoring WGPA’s therapeutic potential for ischemic heart disease. Future research should prioritize elucidating the oral absorption mechanisms of polysaccharides and evaluating the translational feasibility of these findings into clinical applications.

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