Pathogenesis Of Ischemia-reperfusion Injury Research Articles

Novel anti-inflammatory peptide alleviates liver ischemia-reperfusion injury.

Ischemia-reperfusion injury (IRI) remains inevitable in liver surgeries, macrophages play a critical role in the development of IRI, but little is known about the macrophages regulate pathogenesis of IRI. Based on target-guided screening, we identified a small 3 kDa peptide (SjDX5-271) from various schistosome egg-derived peptides that induced M2 macrophage polarization. SjDX5-271 treatment protected the mice against liver IRI through promoting M2 macrophage polarization, the protective effect was abrogated when the macrophages were depleted. Transcriptomic sequencing showed that the TLR signaling pathway was significantly inhibited in macrophages derived from the SjDX5-271 treatment group. We further identified that SjDX5-271 promotes M2 macrophage polarization by inhibiting the TLR4/MyD88/NF-κB signaling pathway and further alleviates hepatic inflammation in liver IRI. Collectively, SjDX5-271 exhibits promising therapeutic effects in IRI and represents a novel therapeutic approach for IRI, even in immune-related diseases. This study revealed the development of a new biologic from the parasite and enhanced our understanding of host-parasite interplay, providing a blueprint for future therapies for immune-related diseases.

Comprehensive Overview of Innovative Strategies in Preventing Renal Ischemia-reperfusion Injury: Insights from Bibliometric and In Silico Analyses.

Ischemia-Reperfusion Injury (IRI) is a complex pathophysiological process with severe consequences, including irreversible loss of renal function. Various intraoperative prevention methods have been proposed to mitigate the harmful effects of warm ischemia and kidney reperfusion. This comprehensive analysis provides an overview of pharmacological agents and intraoperative methods for preventing and treating renal IRI. Our analysis revealed that eplerenone exhibited the highest binding affinity to crucial targets, including Aldehyde Dehydrogenase (AD), Estrogen Receptor (ER), Klotho protein, Mineralocorticoid Receptor (MR), and Toll-Like Receptor 4 (TLR4). This finding indicates eplerenone's potential as a potent preventive agent against IRI, surpassing other available therapeutics like Benzodioxole, Hydrocortisone, Indoles, Nicotinamide adenine dinucleotide, and Niacinamide. In preventing kidney IRI, our comprehensive analysis emphasizes the significance of eplerenone due to its strong binding affinity to key targets involved in the pathogenesis of IRI. This finding positions eplerenone as a promising candidate for further clinical investigation and consideration for future clinical practice. The insights provided in this analysis will assist clinicians and researchers in selecting effective preventive approaches for renal IRI in surgical settings, potentially improving patient outcomes.

Advances in the study of B cells in renal ischemia-reperfusion injury.

Renal ischemia-reperfusion injury (IRI) is a non-negligible clinical challenge for clinicians in surgeries such as renal transplantation. Functional loss of renal tubular epithelial cell (TEC) in IRI leads to the development of acute kidney injury, delayed graft function (DGF), and allograft rejection. The available evidence indicates that cellular oxidative stress, cell death, microvascular dysfunction, and immune response play an important role in the pathogenesis of IRI. A variety of immune cells, including macrophages and T cells, are actively involved in the progression of IRI in the immune response. The role of B cells in IRI has been relatively less studied, but there is a growing body of evidence for the involvement of B cells, which involve in the development of IRI through innate immune responses, adaptive immune responses, and negative immune regulation. Therefore, therapies targeting B cells may be a potential direction to mitigate IRI. In this review, we summarize the current state of research on the role of B cells in IRI, explore the potential effects of different B cell subsets in the pathogenesis of IRI, and discuss possible targets of B cells for therapeutic aim in renal IRI.

Research progress and perspectives of N-methyl-D-aspartate receptor in myocardial and cerebral ischemia-reperfusion injury: A review.

There is an urgent need to find common targets for precision therapy, as there are no effective preventive therapeutic measures for combined clinical heart-brain organ protection and common pathways associated with glutamate receptors are involved in heart-brain injury, but current glutamate receptor-related clinical trials have failed. Ischemia-reperfusion injury (IRI) is a common pathological condition that occurs in multiple organs, including the heart and brain, and can lead to severe morbidity and mortality. N-methyl-D-aspartate receptor (NMDAR), a type of ionotropic glutamate receptor, plays a crucial role in the pathogenesis of IRI. NMDAR activity is mainly regulated by endogenous activators, agonists, antagonists, and voltage-gated channels, and activation leads to excessive calcium influx, oxidative stress, mitochondrial dysfunction, inflammation, apoptosis, and necrosis in ischemic cells. In this review, we summarize current research advances regarding the role of NMDAR in myocardial and cerebral IRI and discuss potential therapeutic strategies to modulate NMDAR signaling to prevent and treat IRI.

The cardioprotective effect of S. africana caerulea/Blue Sage in ischaemia and reperfusion induced oxidative stress.

Background: Since antiquity, alternative herbal remedies, such as S. africana caerulea/Blue Sage (BLS) water infusion extract (WIE) has been used by traditional healers, for the effective treatment of various chronic inflammatory disorders associated with reduced cellular antioxidant defense mechanisms and free radical cellular damage. In the heart, ischaemia-reperfusion (I/R) induced oxidative stress becomes an early crucial event in the pathogenesis of ischaemia-reperfusion injury (I/RI) and subsequent heart failure. Purpose/Aim: To investigate whether BLS WIE treatment during ischaemia and/or reperfusion may be cardioprotective. Study design: Isolated perfused rat hearts were exposed to 35min regional ischaemia (RI) and 60min reperfusion. The BLS WIE was applied: i) for the last 10min of RI (PerT) or ii) from onset of reperfusion (PostT) or iii) both (PerT) + (PostT). Methods: Endpoints were functional recovery and infarct size (IS). In another set of experiments, left ventricles were freeze-clamped after RI and 10min reperfusion for detection of total and phosphorylated p-ERK p44/p42, p-Akt, p-p38-MAPK, p-JNK, Nrf-2, NF-kB, Bax, Bcl-2, Caspase-3, and PGC-1α by Western blot analysis. Results: BLS (PostT) significantly increased ERK p44, p-Akt, Nrf-2, and Bcl-2 levels; significantly decreased p-p38-MAPK as well as p-JNK p46 phosphorylation; did not affect Bax levels and significantly decreased Bax/Bcl-2 ratios. This was associated with significantly reduced Caspase-3 levels and increased PGC-1α phosphorylation, particlarly when BLS WIE was administered as PostT. Conclusion: The administration of polyphenol-rich BLS WIE at different stages of ischaemia and/or reperfusion, activate/inhibit several signaling events simultaneously and mediate cardioprotection in a multitarget manner.

Fucoidan Ameliorates Ferroptosis in Ischemia-reperfusion-induced Liver Injury through Nrf2/HO-1/GPX4 Activation.

Liver ischemia-reperfusion (IR) injury is a common pathological process in liver surgery. Ferroptosis, which is closely related to lipid peroxidation, has recently been confirmed to be involved in the pathogenesis of IR injury. However, the development of drugs that regulate ferroptosis has been slow, and a complete understanding of the mechanisms underlying ferroptosis has not yet been achieved. Fucoidan (Fu) is a sulfated polysaccharide that has attracted research interest due to its advantages of easy access and wide biological activity. In this study, we established models of IR injury using erastin as an activator of ferroptosis, with the ferroptosis inhibitor ferrostatin-1 (Fer-1) as the control. We clarified the molecular mechanism of fucoidan in IR-induced ferroptosis by determining lipid peroxidation levels, mitochondrial morphology, and key pathways in theta were involved. Ferroptosis was closely related to IR-induced hepatocyte injury. The use of fucoidan or Fer-1 inhibited ferroptosis by eliminating reactive oxygen species and inhibiting lipid peroxidation and iron accumulation, while those effects were reversed after treatment with erastin. Iron accumulation, mitochondrial membrane rupture, and active oxygen generation related to ferroptosis also inhibited the entry of nuclear factor erythroid 2-related factor 2 (Nrf2) into the nucleus and reduced downstream heme oxygenase-1 (HO-1) and glutathione peroxidase 4 (GPX4) protein levels. However, fucoidan pretreatment produced adaptive changes that reduced irreversible cell damage induced by IR or erastin. Fucoidan inhibited ferroptosis in liver IR injury via the Nrf2/HO-1/GPX4 axis.

Analysis of potential immune-related genes involved in the pathogenesis of ischemia-reperfusion injury following liver transplantation.

Hepatic ischemia-reperfusion (I/R) injury is an unavoidable pathological process that occurs after liver transplantation. However, the immune-related molecular mechanism still remains unclear. This study aims to further explore the biological mechanisms of immune-related genes in hepatic I/R injury. Gene microarray data was downloaded from the Gene Expression Omnibus (GEO) expression profile database and the differentially expressed genes (DEGs) were taken for intersection. After identifying common DEGs, functional annotation, protein-protein interaction (PPI) network, and modular construction were performed. The immune-related hub genes were obtained, which their upstream transcription factors and non-RNAs were predicted. Validation of the hub genes expression and immune infiltration were performed in a mouse model of hepatic I/R injury. A total of 71 common DEGs were obtained from three datasets (GSE12720, GSE14951, GSE15480). The GO and KEGG enrichment analysis results indicated that immune and inflammatory response played an important role in hepatic I/R injury. Finally, 9 immune-related hub genes were identified by intersecting cytoHubba with immune-related genes, including SOCS3, JUND, CCL4, NFKBIA, CXCL8, ICAM1, IRF1, TNFAIP3, and JUN. Our study revealed the importance of the immune and inflammatory response in I/R injury following liver transplantation and provided new insights into the therapeutic of hepatic I/R injury.

The research development of STAT3 in hepatic ischemia-reperfusion injury.

Ischemia-reperfusion injury (IRI) is a common complication of surgery, which can cause rapid deterioration of the liver function, increase the risk of graft rejection, and seriously affect the prognosis of patients. The signal transducer and activator of transcription 3 (STAT3) protein has been implicated in pathogenesis of IRI. STAT3 influences the mitochondria through multiple pathways and is also involved in apoptosis and other forms of programmed cell death. STAT3 is associated with Janus kinase (JAK), phosphoinositide-3 kinase (PI3K), and heme oxygenase-1 (HO-1) in liver IRI. The STAT3 pathway plays a dual role in IRI as it can also regulate lipid metabolism which may have potential for treating IRI fatty liver. In this review, we summarize research on the function of STAT3 in liver IRI to providereferencesforitsapplicationin theclinic.

Perspectives on mitochondrial relevance in cardiac ischemia/reperfusion injury.

Cardiovascular disease is the most common cause of death worldwide and in particular, ischemic heart disease holds the most considerable position. Even if it has been deeply studied, myocardial ischemia-reperfusion injury (IRI) is still a side-effect of the clinical treatment for several heart diseases: ischemia process itself leads to temporary damage to heart tissue and obviously the recovery of blood flow is promptly required even if it worsens the ischemic injury. There is no doubt that mitochondria play a key role in pathogenesis of IRI: dysfunctions of these important organelles alter cell homeostasis and survival. It has been demonstrated that during IRI the system of mitochondrial quality control undergoes alterations with the disruption of the complex balance between the processes of mitochondrial fusion, fission, biogenesis and mitophagy. The fundamental role of mitochondria is carried out thanks to the finely regulated connection to other organelles such as plasma membrane, endoplasmic reticulum and nucleus, therefore impairments of these inter-organelle communications exacerbate IRI. This review pointed to enhance the importance of the mitochondrial network in the pathogenesis of IRI with the aim to focus on potential mitochondria-targeting therapies as new approach to control heart tissue damage after ischemia and reperfusion process.

Endothelial NO synthase 786T/T polymorphism increases hemorrhagic transformation after endovascular thrombectomy

Background and purposeThis study examined whether the 786 NOS3 polymorphism is associated with the risk of hemorrhagic transformation (HT) in stroke patients with anterior large vessel occlusion (ALVO) treated using endovascular thrombectomy (EVT). MethodsWe performed an observational cohort study that included 118 patients with ALVO who underwent EVT. HT was assessed in follow-up CT and MRI. HT and non-HT patients were compared in terms of the 786 NOS3 polymorphism, flow mediated dilation (FMD) values within 3 days after the stroke, and collateral status based on three grading scales. Demographics, vascular risk factors, additional radiological data including ASPECT score, thrombus length and infarct size, and EVT procedure and outcome variables were also included. ResultsRadiological HT occurred in 55 (46.6%) patients and the 786T/T NOS3 polymorphism was associated with HT (unadjusted OR of 2.33, 95%CI: 1.05–5.20, adjusted OR of 3.14, 95%CI: 1.16–8.54). Collateral status and systemic endothelial function assessed by FMD were not mediators of this relationship as no differences were seen in the median FMD percentage values or collateral status between NOS3 genotypes. ConclusionsOur results suggest that genetic variations affecting the NO pathway, such as the 786 NOS3 polymorphism, may contribute to individual variability in the occurrence of HT and these results support involvement of this pathway in the pathogenesis of ischemia-reperfusion injury after EVT.

Current Status and Prospects of Research on Ischemia-Reperfusion Injury and Ferroptosis.

The pathogenesis of ischemia-reperfusion injury is not fully understood, most of the current clinical treatment methods mainly relieve symptoms, and cannot prevent fundamentally. The mechanism of Ferroptosis has been extensively studied in recent years, but primarily focused on its therapeutic effects on tumors. After careful comparison, it is easy to find that the symptoms of ischemia-reperfusion injury often accompany by increased lipid peroxidation and increased intracellular iron level are the same as the manifestations of iron-dependent non-apoptotic Ferroptosis. Based on this “coincidence”, we launched this survey. After reading a lot of literature, we found that Ferroptosis is the first step of ischemia-reperfusion injury, and cell necrosis and inflammation are the subsequent steps secondary to Ferroptosis. In this review, we have collected and sorted out the current knowledge about the role and targets of Ferroptosis in the process of ischemia-reperfusion injury. And future studies may be biased towards exploring the use of ferroptosis inhibitors in combination with other treatment options.

Transcriptomic Analysis Revealed an Important Role of Peroxisome-Proliferator-Activated Receptor Alpha Signaling in Src Homology Region 2 Domain-Containing Phosphatase-1 Insufficiency Leading to the Development of Renal Ischemia-Reperfusion Injury.

In kidney transplantation, the donor kidney inevitably undergoes ischemia-reperfusion injury (IRI). It is of great importance to study the pathogenesis of IRI and find effective measures to attenuate acute injury of renal tubules after ischemia-reperfusion. Our previous study found that Src homology region 2 domain-containing phosphatase-1 (SHP-1) insufficiency aggravates renal IRI. In this study, we systematically analyzed differences in the expression profiles of SHP-1 (encoded by Ptpn6)-insufficient mice and wild-type mice by RNA-seq. We found that a total of 161 genes showed at least a twofold change, with a false discovery rate <0.05 in Ptpn6 +/mev mice after IRI and 42 genes showing more than a fourfold change. Of the eight genes encoding proteins with immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that bind to Ptpn6, three were upregulated, and five were downregulated. We found that for the differentially expressed genes (DEGs) with a fold change >2, the most significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were the cell division pathway and peroxisome-proliferator activated receptor PPARα signaling pathways. Furthermore, the downregulated genes of the PPARα signaling pathway were mainly related to fatty acid absorption and degradation. Using an agonist of the PPARα signaling pathway, fenofibrate, we found that renal IRI was significantly attenuated in Ptpn6 +/mev mice. In summary, our results show that insufficiency of SHP-1 inhibits the expression of genes in the PPARα signaling pathway, thereby leading to increased reactive oxygen species (ROS) and exacerbating the renal IRI. The PPARα signaling agonist fenofibrate partially attenuates renal IRI induced by SHP-1 insufficiency.

The Pathogenesis of Ischemia-Reperfusion Induced Acute Kidney Injury Depends on Renal Neutrophil Recruitment Whereas Sepsis-Induced AKI Does Not.

Acute kidney injury (AKI) may be induced by different causes, including renal ischemia-reperfusion injury and sepsis, which represent the most common reasons for AKI in hospitalized patients. AKI is defined by reduced urine production and/or increased plasma creatinine. However, this definition does not address the molecular mechanisms of different AKI entities, and uncertainties remain regarding distinct pathophysiological events causing kidney injury in the first place. In particular, sepsis-induced AKI is considered not to be associated with leukocyte infiltration into the kidney, but a direct investigation of this process is missing to this date. In this study, we used two murine AKI models induced by either renal ischemia-reperfusion injury (IRI) or cecal ligation and puncture (CLP) to investigate the contribution of neutrophils to tissue injury and kidney function. By using VEC-Y731F mice, in which neutrophil recruitment is impaired, we analyzed the specific contribution of neutrophil recruitment to the pathogenesis of IRI- and CLP-induced AKI. We observed that the degree of renal injury evaluated by plasma creatinine, urinary biomarkers and histological analyses, following IRI-induction was dependent on neutrophil migration into the kidney, whereas the pathogenesis of CLP-induced AKI was independent of neutrophil recruitment. Furthermore, plasma transfer experiments suggest that the pathogenesis of CLP-induced AKI relies on circulating inflammatory mediators. These results extend our knowledge of the AKI pathogenesis and may help in the development of prophylactic and therapeutic treatments for AKI patients.

Targeting the Hepatic Microenvironment to Improve Ischemia/Reperfusion Injury: New Insights into the Immune and Metabolic Compartments.

Hepatic ischemia/reperfusion injury (IRI) is mainly characterized by high activation of immune inflammatory responses and metabolic responses. Understanding the molecular and metabolic mechanisms underlying development of hepatic IRI is critical for developing effective therapies for hepatic IRI. Recent advances in research have improved our understanding of the pathogenesis of IRI. During IRI, hepatocyte injury and inflammatory responses are mediated by crosstalk between the immune cells and metabolic components. This crosstalk can be targeted to treat or reverse hepatic IRI. Thus, a deep understanding of hepatic microenvironment, especially the immune and metabolic responses, can reveal new therapeutic opportunities for hepatic IRI. In this review, we describe important cells in the liver microenvironment (especially non-parenchymal cells) that regulate immune inflammatory responses. The role of metabolic components in the diagnosis and prevention of hepatic IRI are discussed. Furthermore, recent updated therapeutic strategies based on the hepatic microenvironment, including immune cells and metabolic components, are highlighted.

Irisin: A Promising Target for Ischemia-Reperfusion Injury Therapy.

Ischemia-reperfusion injury (IRI) is defined as the total combined damage that occurs during a period of ischemia and following the recovery of blood flow. Oxidative stress, mitochondrial dysfunction, and an inflammatory response are factors contributing to IRI-related damage that can each result in cell death. Irisin is a polypeptide that is proteolytically cleaved from the extracellular domain of fibronectin type III domain-containing protein 5 (FNDC5). Irisin acts as a myokine that potentially mediates beneficial effects of exercise by reducing oxidative stress, improving mitochondrial fitness, and suppressing inflammation. The existing literature also suggests a possible link between irisin and IRI, involving mechanisms similar to those associated with exercise. This article will review the pathogenesis of IRI and the potential benefits and current limitations of irisin as a therapeutic strategy for IRI, while highlighting the mechanistic correlations between irisin and IRI.

Recent Approaches to Targeting Canonical NFκB Signaling in the Early Inflammatory Response to Renal IRI.

Ischemia reperfusion injury (IRI) is the most common cause of in-hospital AKI and is associated with increased morbidity and mortality. IRI is associated with an early phase of inflammation primarily regulated by the canonical NFκB signaling pathway. Despite recent advances in our understanding of the pathogenesis of IRI, few therapeutic strategies have emerged. The purpose of this manuscript is to review interventions targeting NFκB after IRI.

The Effects of 6-Chromanol SUL-138 during Hypothermic Machine Perfusion on Porcine Deceased Donor Kidneys

Diminishing ischemia-reperfusion injury (IRI) by improving kidney preservation techniques offers great beneficial value for kidney transplant recipients. Mitochondria play an important role in the pathogenesis of IRI and are therefore interesting targets for pharmacological interventions. Hypothermic machine perfusion (HMP), as a preservation strategy, offers the possibility to provide mitochondrial–targeted therapies. This study focuses on the addition of a mitochondrial protective agent SUL—138 during HMP and assesses its effect on kidney function and injury during normothermic reperfusion. In this case, 30 min of warm ischemia was applied to porcine slaughterhouse kidneys before 24 h of non–oxygenated HMP with or without the addition of SUL—138. Functional assessment was performed by 4 h normothermic autologous blood reperfusion. No differences in renal function or perfusion parameters were found between both groups. ATP levels were lower after 30 min of warm ischemia in the SUL–138 group (n.s, p = 0.067) but restored significantly during 24 h of HMP in combination with SUL—138. Aspartate aminotransferase (ASAT) levels were significantly lower for the SUL—138 group. SUL—138 does not influence renal function in this model. Restoration of ATP levels during 24 h of HMP with the addition of SUL in combination with lower ASAT levels could be an indication of improved mitochondrial function.

Ischemia-reperfusion Injury in Allogeneic Liver Transplantation: A Role of CD4 T Cells in Early Allograft Injury.

A major discrepancy between clinical and most experimental settings of liver ischemia-reperfusion injury (IRI) is the allogenicity. In the current study, we first established a murine model of allogeneic orthotopic liver transplantation with extended cold ischemia time (18 h). Roles of CD4 T cells in the pathogenesis of IRI in liver allografts were determined using a depleting anti-CD4 antibody. The clinical relevance of CD4 as a marker of liver IRI was analyzed retrospectively in 55 liver transplant patients. CD4 depletion in both donors and recipients resulted in the most effective protection of liver allografts from IRI, as measured by serum transaminase levels and liver histology. CD4 depletion inhibited IR-induced intragraft neutrophil/macrophage infiltration and proinflammatory gene expressions. Quantitative reverse-transcriptase polymerase chain reaction analysis of human liver biopsies (2 h postreperfusion) revealed that posttransplant, rather than pretransplant, CD4 transcript levels correlated positively with proinflammatory gene expression profile. When we divided patients into subgroups according to intragraft CD4 levels, the high CD4 cohort developed a more severe hepatocellular damage than that with low CD4 levels. CD4 T cells play a key pathogenic role in IRI of allogeneic liver transplants, and intragraft CD4 levels in the early postreperfusion phase may serve as a potential biomarker and therapeutic target to ameliorate liver IRI and improve orthotopic liver transplantation outcomes.

Nanoassemblies of Disulfide-Bridged Bile Acid Dimers as Therapeutics Agents for Hepatic Ischemia/Reperfusion Injury.

Ischemia/reperfusion (IR) injury is induced by the restoration of blood flow to the prolonged ischemic tissues and is considered as the paradoxical exacerbation of ischemic damages. A large amount of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) produced immediately after reperfusion induces oxidative stress, which plays an essential role in the pathogenesis of IR injury. It is therefore critical to suppress oxidative stress for the prevention and treatment of IR injury. Ursodeoxycholic acid (UDCA), one of the tertiary bile acids, promotes the generation of antioxidant glutathione (GSH) and also exerts hepatoprotective, cytoprotective, and antiapoptotic effects. However, the clinical uses of UDCA are limited mainly by its poor water solubility and low bioavailability. In this study, by exploiting the concept of self-assembling disulfide-bridged dimeric prodrugs, we developed a disulfide-bridged UDCA dimer (ssUDCA) as a therapeutic agent of hepatic IR injury. ssUDCA could self-assemble into stable nanospheres under aqueous conditions, scavenge H2O2, and exert anti-inflammatory and antiapoptotic activities. In a mouse model of hepatic IR injury, ssUDCA (5 mg/kg) significantly alleviated the IR injury by suppressing ROS production and inhibiting proinflammatory cytokines. Therefore, our findings offer a promising strategy for the effective treatment of hepatic IR injury and also provide deep insights into the impact of disulfide-bridged UDCA nanoassemblies in pharmaceutical applications.

Abstract 204: Modification of AIFm2 By 4HNE Leads to Retrograde Stress Signaling During Ischemia- Reperfusion Injury in Heart

Myocardial infarction is a leading cause of death worldwide and occurs due to blockage in blood supply to the heart. Re-establishment of blood flow after a brief period of ischemia leads to paradoxical exacerbation of the cardiomyocyte and its death. This phenomenon is known as ischemia-reperfusion injury. Major evidence in the pathogenesis of ischemia-reperfusion injury is due to oxidative stress, which is an imbalance between reactive oxygen species (ROS) and antioxidants. Membrane consisting of polyunsaturated fatty acid is attacked by ROS leading to lipid peroxidation and the generation of one of the toxic aldehydes 4-hydroxynonenal (4-HNE). Evidence suggests that 4-HNE increases during an ischemia-reperfusion injury in the heart. Apoptosis-inducing factor, mitochondrion-associated 2 (AIFM2) is a mitochondrial located oxidoreductase that participates in caspase-independent apoptosis. In this study, we sought to identify the role of 4-HNE in regulating AIFm2 translocation and cardiomyocyte death during an ischemia-reperfusion injury in the heart. Following ischemia both RNA and protein expression of AIFm2 significantly increased in the ischemic heart compared to sham. Also, 4-HNE adducted AIFm2 translocated from mitochondria to the nucleus shown by western blot analysis in ischemic heart. The mass spectrometric analysis was done to see the modification site on AIFm2 by 4-HNE and revealed that His 174 and Cys 187 are two sites on AIFm2 where 4-HNE adduction occurred. To identify the modification site responsible for AIFm2 translocation we performed site-direct mutagenesis in H9C2 cardiomyocyte, where Histidine 174 was replaced by arginine and Cys 187 was replaced by threonine. When the ischemia-reperfusion injury was induced, only Histidine 174 mutant failed to translocate to the nucleus indicating His 174 modification by 4-HNE was responsible for AIFm2 translocation. To further support the transport mechanism, protein expression of Importin; an adaptor protein responsible for the transfer of proteins to the nucleus was increased in the ischemic heart compared to sham. Collectively, those results for the first time identify the unique role of 4-HNE modification on AIFm2 protein during an ischemia-reperfusion injury in the heart.