Pharmacological Effects of Ginsenoside Rg3 on MI/R and the Potential Mechanisms
Introduction
Myocardial ischemia/reperfusion (MI/R) can damage the heart muscle, which may contribute to further cardiomyocyte death. Following percutaneous coronary intervention therapy, patients with MI/R-induced injury show a hospital death rate of 6%-14%, as indicated in a clinical report. Recent research unravels that MI/R injury is accompanied by ferroptosis, a newly discovered iron-dependent programmed cell death. Remarkably, ginsenoside Rg3, a constituent of ginsenosides extracted from Panax ginseng, can attenuate MI/R-induced damage via targeting ferroptosis, providing new insight onto the prevention and treatment of heart diseases.
About ferroptosis
Ferroptosis is a novel and unique iron-dependent non-apoptosis-regulated form of cell death, which is characterized by oxidative damage to phospholipids and is related to iron ion metabolism, lipid oxidative metabolism and glutathione (GSH) metabolic pathways. Oxidative stress triggered by excessive ROS accumulation is an essential initiator of ferroptosis. Almost all genes involved in ferroptosis are regulated by Nrf2.
Pharmacological effects of ginsenoside Rg3 on MI/R
10 and 20 mg/kg ginsenoside Rg3 improves the cardiac function damaged by MI/R, as manifested by the increases in the left ventricular ejection reduction fraction (LVEF) and left ventricular shortening reduction (LVFS). Morphologically, MI/R disrupts myofiber structure and leads to inflammatory cell infiltration. However, ginsenoside Rg3 prevents the changes in myofiber structure, reduces the recruitment of inflammatory cells, and significantly reduces the MI/R-induced myocardial infarction area.
Mechanisms underlying the cardio-protective effect of ginsenoside Rg3
Ginsenoside Rg3 can improve cardiac function and attenuate MI/R-induced ferroptosis via the keap1/Nrf2/GPX4 signaling pathway. Notably, Keap1 is a chaperone protein with an essential role in maintaining redox homeostasis in vivo. Nrf2 is a transcriptional regulator that can activate adaptive responses like anti-oxidative stress and ferroptosis by transcriptionally inducing a multitude of antioxidant enzymes such as GPX4. GPX4 catalyzes the conversion of lipid peroxides to the lipohydrol form, which plays a vital in ferroptosis.
Conclusion
The cardio-protective effect of ginsenoside Rg3 can be realized by repressing ferroptosis via Keap1/Nrf2/GPX4 signaling pathway. These findings further unveil that ginsenoside Rg3 may act as a promising candidate to combat heart disease.
Reference
Zhong G, Chen J, Li Y, et al. Ginsenoside Rg3 attenuates myocardial ischemia/reperfusion-induced ferroptosis via the keap1/Nrf2/GPX4 signaling pathway. BMC Complement Med Ther. 2024;24(1):247. Published 2024 Jun 26. doi:10.1186/s12906-024-04492-4
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