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

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 tRNA^UTuT6 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.

SUBMITTER: Liu C

PROVIDER: S-EPMC8443360 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMyocardial cell death resulting from ischemia-reperfusion (I/R) injury has been a predominant contributor to morbidity and mortality globally. The mitochondria-centered mechanism plays an important role in the formation of I/R injury. This study intended to discuss the protective mechanism of Shen Yuan Dan (SYD) on cardiomyocytes hypoxia-reoxygenation (H/R) injury via the regulation of mitochondrial quality control (MQC). Additionally, this study clarified the mechanism by which SYD suppressed mitophagy activity through the suppression of the PTEN-induced kinase 1 (PINK1)/Parkin pathway.MethodsTo induce cellular injury, H9c2 cardiomyocytes were exposed to H/R stimulation. Following the pretreatment with SYD, cardiomyocytes were subjected to H/R stimulation. Mitochondrial membrane potential (MMP), adenosine triphosphate (ATP), superoxide dismutase (SOD), and methane dicarboxylic aldehyde (MDA) were detected to evaluate the degree of cardiomyocyte mitochondrial damage. Laser confocal microscopy was applied to observe the mitochondrial quality, and the messenger (mRNA) levels of mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), optic atrophy protein 1 (Opa1), dynamin-related protein 1 (Drp1), fission 1 (Fis1), and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in cardiomyocytes were assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Western blotting was employed for the estimation of light chain 3 (LC3)-I, LC3-II, PINK1, and Parkin in cardiomyocytes.ResultsIt was discovered that SYD pretreatment elevated MMP in H/R injury cardiomyocytes, enhanced ATP content, activated SOD activity, and reduced MDA level. SYD treatment increased the mRNA levels of Mfn1, Mfn2, Opa1 and PGC-1α decreased the mRNA levels of Drp1 and Fis1, and reduced the protein levels of LC3, PINK1, and Parkin.ConclusionsSYD plays a protective role in H/R injury to cardiomyocytes by regulating mitochondrial quality. Meanwhile, SYD may inhibit mitophagy activity through inhibiting the PINK1/Parkin pathway. This study provides insights into the underlying mechanism of SYD in alleviating myocardial I/R injury.

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

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