Dataset Information

Effect of Mitochondrial Antioxidant (Mito-TEMPO) on Burn-Induced Cardiac Dysfunction.

ABSTRACT:

Background

Imbalance of oxidants/antioxidants results in heart failure, contributing to mortality after burn injury. Cardiac mitochondria are a prime source of reactive oxygen species (ROS), and a mitochondrial-specific antioxidant may improve burn-induced cardiomyopathy. We hypothesize that the mitochondrial-specific antioxidant, Triphenylphosphonium chloride (Mito-TEMPO), could protect cardiac function after burn.

Study design

Male rats had a 60% total body surface area (TBSA) scald burn injury and were treated with/without Mito-TEMPO (7 mg/kg-1, intraperitoneal) and harvested at 24 hours post-burn. Echocardiography (ECHO) was used for measurement of heart function. Masson Trichrome and hematoxylin and eosin (H & E) staining were used for cardiac fibrosis and immune response. Qualitative polymerase chain reaction (qPCR) was used for mitochondrial DNA replication and gene expression.

Results

Burn-induced cardiac dysfunction, fibrosis, and mitochondrial damage were assessed by measurement of mitochondrial function, DNA replication, and DNA-encoded electron transport chain-related gene expression. Mito-TEMPO partially improved the abnormal parameters. Burn-induced cardiac dysfunction was associated with crosstalk between the NFE2L2-ARE pathway, PDE5A-PKG pathway, PARP1-POLG-mtDNA replication pathway, and mitochondrial SIRT signaling.

Conclusions

Mito-TEMPO reversed burn-induced cardiac dysfunction by rescuing cardiac mitochondrial dysfunction. Mitochondria-targeted antioxidants may be an effective therapy for burn-induced cardiac dysfunction.

SUBMITTER: Wen JJ

PROVIDER: S-EPMC8753741 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Effect of Mitochondrial Antioxidant (Mito-TEMPO) on Burn-Induced Cardiac Dysfunction.

Wen Jake J JJ Williams Taylor P TP Cummins Claire B CB Colvill Kayla M KM Radhakrishnan Geetha L GL Radhakrishnan Ravi S RS

Journal of the American College of Surgeons 20210107 4

<h4>Background</h4>Imbalance of oxidants/antioxidants results in heart failure, contributing to mortality after burn injury. Cardiac mitochondria are a prime source of reactive oxygen species (ROS), and a mitochondrial-specific antioxidant may improve burn-induced cardiomyopathy. We hypothesize that the mitochondrial-specific antioxidant, Triphenylphosphonium chloride (Mito-TEMPO), could protect cardiac function after burn.<h4>Study design</h4>Male rats had a 60% total body surface area (TBSA) s ...[more]

PMID: 33421567

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Project description:AimsThe mitochondria are important sources of reactive oxygen species (ROS) in the heart. Mitochondrial ROS production has been implicated in the pathogenesis of diabetic cardiomyopathy, suggesting that therapeutic strategies specifically targeting mitochondrial ROS may have benefit in this disease. We investigated the therapeutic effects of mitochondria-targeted antioxidant mito-TEMPO on diabetic cardiomyopathy.MethodsThe mitochondria-targeted antioxidant mito-TEMPO was administrated after diabetes onset in a mouse model of streptozotocin-induced type-1 diabetes and type-2 diabetic db/db mice. Cardiac adverse changes were analyzed and myocardial function assessed. Cultured adult cardiomyocytes were stimulated with high glucose, and mitochondrial superoxide generation and cell death were measured.ResultsIncubation with high glucose increased mitochondria superoxide generation in cultured cardiomyocytes, which was prevented by mito-TEMPO. Co-incubation with mito-TEMPO abrogated high glucose-induced cell death. Mitochondrial ROS generation, and intracellular oxidative stress levels were induced in both type-1 and type-2 diabetic mouse hearts. Daily injection of mito-TEMPO for 30 days inhibited mitochondrial ROS generation, prevented intracellular oxidative stress levels, decreased apoptosis and reduced myocardial hypertrophy in diabetic hearts, leading to improvement of myocardial function in both type-1 and type-2 diabetic mice. Incubation with mito-TEMPO or inhibition of Nox2-containing NADPH oxidase prevented oxidative stress levels and cell death in high glucose-stimulated cardiomyocytes. Mechanistic study revealed that the protective effects of mito-TEMPO were associated with down-regulation of ERK1/2 phosphorylation.ConclusionsTherapeutic inhibition of mitochondrial ROS by mito-TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in diabetic mice. Thus, mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications.

Project description:Abstract Introduction The cytokine cascade is a prime factor in inflammation following burn injury, leading to cardiac dysfunction. Studies on immune-related key cardiac genes after burn injury remain limited. The TLRs act individually or as heterodimers, interacting with adaptor proteins to initiate MyD88 or TICAM1 (TRIF) dependent responses. This results in signaling cascades through NFkB, which activates downstream JNK/p38 signaling or cytokine secretion. Dysregulation of TLR and related signaling pathways has severe consequences and is implicated in autoimmune diseases and chronic inflammation. The objective of this study is to identify the immune-related key genes and explore the pathways by microarray specific to members of the TLR signaling family as well as adaptor and effector proteins, and downstream members of TLR activation including the NFkB, JNK/p38, IRF and JAK/STAT signaling pathways. Methods The microarray was applied to profile expression of 84 genes inTLR-mediated signal transduction and innate immunity. The Qiagen web-based tools in GeneGlobe Data Analysis Center was used to analyze burn-induced up-regulation of these genes. String-DB version 11.5 was employed to analyze differentially expressed gene function and interaction. Real-time qPCR was utilized to validate the data. GO enrichment analysis (FDR< 0.05) using "clusterProfiler" predicted the roles of immune-key genes in the 3 aspects of biological processes (BP), cellular components (CC), and molecular functions (MF). The biological pathway analysis was performed to obtain the pathways. The protein-protein interaction (PPI) network was built using "Multiple Protein" of the string database (http://stringdb.org/, version 15.0). The DEGs were visualized by using the qPCR. Results 32 up-regulated genes were identified. Functional enrichment analysis showed that these genes were enriched in cytokine receptor activity, immune receptor activity, and integrin family cell surface interactions.14 of 32 genes belong to the TLR signaling pathway; 5 of 32 genes to cytokines and inflammation; 5 of 32 genes belong to apoptosis; 6 in the MARP signaling pathway; 4 genes belong to the IL-1 signaling pathway; 4 genes in the IL-6 signaling pathway); 3 genes in toIL-2 signaling pathway and 3 genes belong to oxidative stress responses. Process study demonstrated the genes are associated with regulation of cytokine production (GO:0001817), immune response (GO:0006955), and defense response (GO:0006952). Conclusions This study provides evidence that microarray plays a role in identification of burn-induced cardiac dysfunction DEGs. Deep analysis of up-regulated genes after burn injury supported the idea that the proinflammatory cascade results in cardiac inflammation.

Dataset Information

Effect of Mitochondrial Antioxidant (Mito-TEMPO) on Burn-Induced Cardiac Dysfunction.

Background

Study design

Results

Conclusions

Publications

Effect of Mitochondrial Antioxidant (Mito-TEMPO) on Burn-Induced Cardiac Dysfunction.

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