Xanthohumol Protects the Rat Myocardium against Ischemia/Reperfusion Injury-Induced Ferroptosis.

Jian-Hong Lin,Yi-Shun Wang,Jui-Chih Chang,Pei-Ching Ting,Kun-Ta Yang,Yu-Po Luo,Wen-Sen Lee,Ding-Jyun Lin,Yanwei Xing

doi:10.1155/2022/9523491

Abstract

Ferroptosis is an iron-dependent form of cell death caused by the inactivation of glutathione peroxidase 4 (GPX4) and accumulation of lipid peroxides. Ferroptosis has been found to participate in the ischemia-reperfusion (I/R) injury, leading to heart dysfunction and myocardial cell death. Xanthohumol (XN), a prenylated flavonoid isolated from Humulus lupulus, has multiple pharmacological activities, such as anti-inflammatory and antioxidant. This study is aimed at investigating whether XN could attenuate the I/R-induced ferroptosis in cardiomyocytes and the underlying mechanisms. Cardiomyocytes were treated with Fe-SP and RSL3, and the rat hearts were treated with I/R. The results from the present study show that XN was able to protect cardiomyocytes against Fe-SP- and RSL3-induced ferroptotic cell death by decreasing the production of lipid peroxidation and ROS, chelating iron, reducing the NRF2 protein level, and modulating the protein levels of GPX4. Moreover, XN significantly decreased the mRNA levels of ferroptosis markers, Ptgs2 and Acsl4, and the protein levels of ACSL4 and NRF2 and modulated the protein levels of GPX4 in I/R-treated hearts. The findings from the present study suggest that XN might have the therapeutic potential for the I/R-induced ferroptosis injury.

Highlights

According to the World Health Organization, ischemic heart disease is the first leading cause of death worldwide [1]
Our results show that both Fer-1 (1 μM) and Lip-1 (2 μM) significantly inhibited the Fe-SP- and RSL3induced ferroptotic cell death, respectively (Figures 1(a) and 1(b), right panel)
Ferroptosis is an iron-dependent form of cell death associated with increased lipid peroxidation

Summary

Introduction

According to the World Health Organization, ischemic heart disease is the first leading cause of death worldwide [1]. Reperfusion is the definitive treatment for acute ischemic heart disease [2]. There is no effective therapy to prevent heart damage caused by ischemia-reperfusion (I/ R) injury (IRI). IRI may cause massive cardiomyocyte death, which is a major cause of cardiac dysfunction, leading to cardiac arrhythmias, heart failure, and death [3]. The deregulation of iron homeostasis has an important contribution to increasing intracellular free iron in cardiac cells [5]. The iron ion can enhance the generation of reactive oxygen species (ROS) by Fenton reaction, subsequently increasing cell damage through the attack of lipids to induce ferroptosis, which differs from apoptosis, necrosis, or autophagy [6]

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Conclusion