Protective Effects and Mechanisms of Recombinant Human Glutathione Peroxidase 4 on Isoproterenol-Induced Myocardial Ischemia Injury.

Tianjiao Zhang,Shaopeng Niu,Bozhao Li,Giuseppe Cirillo,Qi Yan,Chang Liu,Jingyan Wei,Yiding Zhao,Changhao Xiong

doi:10.1155/2021/6632813

Abstract

Ischemic heart disease (IHD) is a cardiovascular disease with high fatality rate, and its pathogenesis is closely related to oxidative stress. Reactive oxygen species (ROS) in oxidative stress can lead to myocardial ischemia (MI) injury in many ways. Therefore, the application of antioxidants may be an effective way to prevent IHD. In recent years, glutathione peroxidase 4 (GPx4) has received increasing attention due to its antioxidant effect. In a previous study, we used the new chimeric tRNAUTuT6 to express highly active recombinant human GPx4 (rhGPx4) in amber-less Escherichia coli. In this study, we established an isoproterenol- (ISO-) induced MI injury model in rats and an in vitro model to research the protective effect and mechanism of rhGPx4 on MI injury. The results showed that rhGPx4 could reduce the area of myocardial infarction and ameliorate the pathological injury of heart tissue, significantly reduce ISO-induced abnormalities on electrocardiogram (ECG) and cardiac serum biomarkers, protect mitochondrial function, and attenuate cardiac oxidative stress injury. In an in vitro model, the results also confirmed that rhGPx4 could inhibit ISO-induced oxidative stress injury and cardiomyocyte apoptosis. The mechanism of action of rhGPx4 involves not only the inhibition of lipid peroxidation by eliminating ROS but also keeping a normal level of endogenous antioxidant enzymes by eliminating ROS, thereby preventing oxidative stress injury in cardiomyocytes. Additionally, rhGPx4 could inhibit cardiomyocyte apoptosis through a mitochondria-dependent pathway. In short, rhGPx4, a recombinant antioxidant enzyme, can play an important role in the prevention of IHD and may have great potential for application.

Highlights

Ischemic heart disease (IHD) has been one of the leading causes of mortality in the world [1]
Oxidative stress is closely related to the occurrence and development of Myocardial ischemia (MI), and cardiomyocytes can produce a large amount of reactive oxygen species (ROS) under ischemia and hypoxia
The results were in accordance with in vivo studies. These results indicated that recombinant human GPx4 (rhGPx4) could inhibit lipid peroxidation and maintain a normal level of endogenous antioxidant enzymes by eliminating ROS

Summary

Introduction

Ischemic heart disease (IHD) has been one of the leading causes of mortality in the world [1]. Oxidative stress is closely related to the occurrence and development of MI, and cardiomyocytes can produce a large amount of reactive oxygen species (ROS) under ischemia and hypoxia [3]. Excessive ROS can cause cardiac oxidative stress injury, leading to abnormalities in the myocardial structure and function [4, 5]. Glutathione peroxidase 4 (GPx4) is a seleniumcontaining antioxidant enzyme in monomeric form. It cannot only catalyze small molecular hydroperoxide and reduce phospholipid hydroperoxide in the membrane and lipoprotein to inhibit lipid peroxidation [6, 7]. We successfully developed a new chimeric tRNAUTuT6 method to efficiently express glutathione peroxidase (GPx) in amber-less Escherichia coli (E. coli) based on the work of the Dieter Söll group at Yale University [12].

Methods

Discussion

Conclusion