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Aim: This study aimed to construct an ischemic cardiomyocyte-targeted and ROS-responsive drug release system to reduce myocardial ischemia-reperfusion injury (MI/RI). Methods: We constructed thioketal (TK) and cardiac homing peptide (CHP) dual-modified liposomes loaded with puerarin (PUE@TK/CHP-L), which were expected to deliver drugs precisely into ischemic cardiomyocytes and release drugs in response to the presence of high intracellular ROS levels. The advantages of PUE@TK/CHP-L were assessed by cellular pharmacodynamics, in vivo fluorescence imaging and animal pharmacodynamics. Results: PUE@TK/CHP-L significantly inhibited apoptosis and ferroptosis in H/R-injured cardiomyocytes and also actively targeted ischemic myocardium. Based on these advantages, PUE@TK/CHP-L could significantly enhance the drug's ability to attenuate MI/RI. Conclusion: PUE@TK/CHP-L had potential clinical value in the precise treatment of MI/RI. Article highlights Myocardial ischemia-reperfusion injury (MI/RI) is a series of pathological changes caused by revascularisation after myocardial infarction, for which there is no effective treatment. Excessive production of reactive oxygen species (ROS) is an important predisposing factor for MI/RI. Apoptosis and ferroptosis of cardiomyocytes are important pathological mechanisms of myocardial ischemia-reperfusion injury and both are closely related to excessive intracellular ROS. We have successfully synthesized ROS-responsive and cardiac-targeted liposomes loaded with puerarin (PUE@TK/CHP-L). It was found that PUE@TK/CHP-L could target ischemic myocardium. In vivo and ex vivo results showed that PUE@TK/CHP-L can effectively reduce the level of myocardial oxidative stress and decrease cardiomyocyte apoptosis and ferroptosis. These results suggested that PUE@TK/CHP-L could hopefully be a promising drug carrier for mitigating MI/RI. [ABSTRACT FROM AUTHOR]

Myocardial ischemia-reperfusion injury (MIRI) is a significant factor in the development of cardiac dysfunction following a myocardial infarction. Ferroptosis, a type of regulated cell death driven by iron and marked by lipid peroxidation, has garnered growing interest for its crucial involvement in the pathogenesis of MIRI.This review comprehensively examines the mechanisms of ferroptosis, focusing on its regulation through iron metabolism, lipid peroxidation, VDAC signaling, and antioxidant system dysregulation. We also compare ferroptosis with other forms of cell death to highlight its distinct characteristics. Furthermore, the involvement of ferroptosis in MIRI is examined with a focus on recent discoveries concerning ROS generation, mitochondrial impairment, autophagic processes, ER stress, and non-coding RNA regulation. Lastly, emerging therapeutic strategies that inhibit ferroptosis to mitigate MIRI are reviewed, providing new insights into potential clinical applications. [ABSTRACT FROM AUTHOR]

Migratory cells exist in the heart, such as immune cells, fibroblasts, endothelial cells, etc. During myocardium injury, such as ischemia–reperfusion (MIRI), cells migrate to the site of injury to perform repair functions. However, excessive aggregation of these cells may exacerbate damage to the structure and function of the heart, such as acute myocarditis and myocardial fibrosis. Myocardial injury releases exosomes, which are a type of vesicle with signal transduction function and the miRNA carried by exosomes can control cell migration function. Therefore, regulating this migratory cell population through cardiac-derived exosomal miRNA is crucial for protecting and maintaining cardiac function. Through whole transcriptome RNA sequencing, exosomal miRNA sequencing and single-cell dataset analysis, we (1) determined the potential molecular regulatory role of the lncRNA‒miRNA‒mRNA axis in MIRI, (2) screened four important exosomal miRNAs that could be released by cardiac tissue, and (3) screened seven genes related to cell locomotion that are regulated by four miRNAs, among which Tradd and Ephb6 may be specific for promoting migration of different cells of myocardial tissue in myocardial infarct. We generated a core miRNA‒mRNA network based on the functions of the target genes, which may be not only a target for cardiac repair but also a potential diagnostic marker for interactions between the heart and other tissues or organs. In conclusion, we elucidated the potential mechanism of MIRI in cardiac remodeling from the perspective of cell migration, and inhibition of cellular overmigration based on this network may provide new therapeutic targets for MIRI and to prevent MIRI from developing into other diseases. [ABSTRACT FROM AUTHOR]

Myocardial ischemia-reperfusion injury (MIRI) is a significant factor in the development of cardiac dysfunction following a myocardial infarction. Ferroptosis, a type of regulated cell death driven by iron and marked by lipid peroxidation, has garnered growing interest for its crucial involvement in the pathogenesis of MIRI. This review comprehensively examines the mechanisms of ferroptosis, focusing on its regulation through iron metabolism, lipid peroxidation, VDAC signaling, and antioxidant system dysregulation. We also compare ferroptosis with other forms of cell death to highlight its distinct characteristics. Furthermore, the involvement of ferroptosis in MIRI is examined with a focus on recent discoveries concerning ROS generation, mitochondrial impairment, autophagic processes, ER stress, and non-coding RNA regulation. Lastly, emerging therapeutic strategies that inhibit ferroptosis to mitigate MIRI are reviewed, providing new insights into potential clinical applications. [ABSTRACT FROM AUTHOR]

Myocardial ischemia-reperfusion (MI/RI) injury is a type of cardiac damage that occurs during the reperfusion of myocardial tissue following a period of ischemia. While perillaldehyde (PAE) has been suggested to have anti-inflammatory properties, its effects on MI/RI remain unclear. This study aimed to evaluate the impact of PAE on MI/RI injury. To simulate MI/RI in vivo, an ischemia-reperfusion (I/R) rat model was established. The levels of lactate dehydrogenase (LDH), creatine kinase (CK) and oxidative stress-related factors were measured using commercial assay kits. The myocardial infarct size was assessed through triphenyl tetrazolium chloride (TTC) staining. The expression levels of miR-133a-3p and inflammatory factors were determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Myocardial cell apoptosis was evaluated by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) staining, and the protein levels of BCL2 associated X (Bax), BCL2 apoptosis regulator (Bcl-2) and mitogen-activated protein kinase 1 (MAPK1) were analyzed by Western blot. PAE could effectively alleviate MI/RI-induced myocardial injury by reducing the levels of LDH and CK, as well as decreasing infarct size. It also mitigated the myocardial inflammatory response by lowering the levels of proinflammatory factors. Additionally, PAE reduced oxidative stress and apoptosis in myocardial cells. Further experiments showed that these protective effects of PAE were associated with the up-regulation of miR-133a-3p, which in turn decreased MAPK1 levels. In conclusion, PAE attenuated MI/RI-induced myocardial injury, inflammatory response, oxidative stress and apoptosis in rats by inhibiting MAPK1, indicating that PAE may effectively reduce myocardial damage caused by I/R injury. [ABSTRACT FROM AUTHOR]

Objective: We aim to investigate the association between prognosis and outcomes following myocardial ischemia-reperfusion injury, as well as peripheral blood levels of NLRP3 and the triglyceride-glucose index (TyG). Methods: A total of 100 patients who underwent emergency coronary intervention following myocardial infarction confirmed by coronary angiography at our hospital between October 2021 and May 2023 were included in this study. Patients were stratified into two groups based on their prognoses: the control group (n = 73), which did not experience new myocardial infarctions or require hospitalization for heart failure or suffer sudden cardiac death post-interventional treatment; and the observation group (n = 27), which experienced one or more cardiovascular events post-treatment. Patient demographics were obtained from clinical records while biochemical analyses assessed peripheral blood triglycerides, blood glucose levels, and TyG index. Additionally, ELISA measurements determined levels of NLRP3 as well as inflammatory factors IL-6, TNF-α, and CRP in peripheral blood samples. Cardiac function was evaluated according to NYHA standards. Univariable Cox regression analysis identified factors influencing patient prognosis while Pearson correlation analysis examined relationships among prognosis, outcomes following myocardial ischemia-reperfusion injury, TyG index, and peripheral blood NLRP3. Results: No significant differences were observed in the general characteristics between the two patient groups (P > 0.05). However, the observation group exhibited higher levels of peripheral blood triglycerides, blood glucose, and TyG index compared to the control group (P < 0.05). Additionally, levels of NLRP3 and inflammatory factors IL-6, TNF-α, and CRP were elevated in the observation group compared to the control group (P < 0.05). Cardiac function impairment was more pronounced in the observation group (P < 0.05). Notably, TyG index and peripheral blood NLRP3 demonstrated higher risk ratios compared to other biomarkers (P < 0.05), indicating their significance in prognosis and outcomes. Elevated levels of NLRP3 and TyG index were associated with poorer recovery of cardiac function, increased rehospitalization rates, and higher mortality (P < 0.05). Conclusion: Elevated NLRP3 levels and an increased TyG index are strongly associated with impaired cardiac function and heightened risk of cardiovascular events. These findings suggest that these biomarkers may serve as crucial prognostic indicators following myocardial ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Ferroptosis is a new way of cell death which is reported to participate in the pathology of myocardial ischemia–reperfusion (MI/R) injury, but it's mechanism remains unclear. The present investigation is to study the emerging role of long non-coding RNA (lncRNA) regulator of reprogramming (ROR) in cardiomyocyte ferroptosis after hypoxia/reoxygenation (H/R) administration. RT-qPCR and/or Western blot methods were performed to examine the gene/or protein levels, and CCK-8, ELISA, and DCFH-DA staining determined the cellular viability and ferroptosis. Dual-luciferase and RNA immunoprecipitation were applied to verify molecular interaction. LncRNA ROR and miR-769-5p were overexpressed and reduced in blood samples from MI patients and H/R-treated AC16 cells, respectively. Mechanistically, lncROR sponged to miR-769-5p, thus upregulating CBX7 expression. Functional experiments presented that lncRNA ROR silence mitigated H/R-stimulated inflammatory damage, oxidative stress, and ferroptosis in AC16 cells, whereas these roles could be reversed by co-downregulation of miR-769-5p or co-overexpression of CBX7. These data uncovered that lncRNA ROR prevented against H/R-induced cardiomyocyte ferroptosis by modulating miR-769-5p/CBX7 signaling, emphasizing the therapeutic value of lncRNA ROR in MI/R injury. [ABSTRACT FROM AUTHOR]

Delivering therapeutic agents efficiently to inflamed regions remains an intractable challenge following myocardial ischemia-reperfusion injury (MI/RI) due to the transient nature of the enhanced permeability and retention effect, which disappears after 24 h. Leveraging the inflammation-homing and plasticity properties of circulating monocytes (MN) as hitchhiking carriers and further inducing their polarization into anti-inflammatory phenotype macrophages upon reaching the inflamed sites is beneficial for MI/RI therapy. Herein, DSS/PB@BSP nanoparticles capable of clearing reactive oxygen species and inhibiting inflammation were developed by employing hollow Prussian blue nanoparticles (PB) as carriers to encapsulate betamethasone sodium phosphate (BSP) and further modified with dextran sulfate sodium (DSS), a targeting ligand for the scavenger receptor on MN. This formulation was internalized into MN as living cell drug depots, reprogramming them into anti-inflammation type macrophages to inhibit inflammation. In vitro assessments revealed the successful construction of the nanoparticle. In a murine MI/RI model, circulating MN laden with these nanoparticles significantly enhanced drug delivery and accumulation at the cardiac injury site, exhibiting favorable therapeutic ability and promoting M2-biased differentiation. Our study provides an effective approach with minimally invasion and biosecurity that makes this nanoplatform as a promising candidate for immunotherapy and clinical translation in the treatment of MI/RI. [Display omitted] [ABSTRACT FROM AUTHOR]

MicroRNAs are single-stranded non-coding RNAs that participate in post-transcriptional regulation of gene expression, it is involved in the regulation of apoptosis after myocardial ischemia–reperfusion injury. For example, the alteration of mitochondrial structure is facilitated by MicroRNA-1 through the regulation of apoptosis-related proteins, such as Bax and Bcl-2, thereby mitigating cardiomyocyte apoptosis. MicroRNA-21 not only modulates the expression of NF-κB to suppress inflammatory signals but also activates the PI3K/AKT pathway to mitigate ischemia–reperfusion injury. Overexpression of MicroRNA-133 attenuates reactive oxygen species (ROS) production and suppressed the oxidative stress response, thereby mitigating cellular apoptosis. MicroRNA-139 modulates the extrinsic death signal of Fas, while MicroRNA-145 regulates endoplasmic reticulum calcium overload, both of which exert regulatory effects on cardiomyocyte apoptosis. Therefore, the article categorizes the molecular mechanisms based on the three classical pathways and multiple signaling pathways of apoptosis. It summarizes the targets and pathways of MicroRNA therapy for ischemia–reperfusion injury and analyzes future research directions. [ABSTRACT FROM AUTHOR]

Background: Myocardial ischemia-reperfusion injury (MI/RI) is an unavoidable risk event for acute myocardial infarction, with ferroptosis showing close involvement. We investigated the mechanism of MI/RI inducing myocardial injury by inhibiting the ferroptosis-related SLC7A11/glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathway and activating mitophagy. Methods: A rat MI/RI model was established, with myocardial infarction area and injury assessed by TTC and H&E staining. Rat cardiomyocytes H9C2 were cultured in vitro, followed by hypoxia/reoxygenation (H/R) modeling and the ferroptosis inhibitor lipoxstatin-1 (Lip-1) treatment, or 3-Methyladenine or rapamycin treatment and overexpression plasmid (oe-SLC7A11) transfection during modeling. Cell viability and death were evaluated by CCK-8 and LDH assays. Mitochondrial morphology was observed by transmission electron microscopy. Mitochondrial membrane potential was detected by fluorescence dye JC-1. Levels of inflammatory factors, reactive oxygen species (ROS), Fe2+, malondialdehyde, lipid peroxidation, GPX4 enzyme activity, glutathione reductase, GSH and glutathione disulfide, and SLC7A11, GPX4, LC3II/I and p62 proteins were determined by ELISA kit, related indicator detection kits and Western blot. Results: The ferroptosis-related SLC7A11/GSH/GPX4 pathway was repressed in MI/RI rat myocardial tissues, inducing myocardial injury. H/R affected GSH synthesis and inhibited GPX4 enzyme activity by down-regulating SLC7A11, thus promoting ferroptosis in cardiomyocytes, which was averted by Lip-1. SLC7A11 overexpression improved H/R-induced cardiomyocyte ferroptosis via the GSH/GPX4 pathway. H/R activated mitophagy in cardiomyocytes. Mitophagy inhibition reversed H/R-induced cellular ferroptosis. Mitophagy activation partially averted SLC7A11 overexpression-improved H/R-induced cardiomyocyte ferroptosis. H/R suppressed the ferroptosis-related SLC7A11/GSH/GPX4 pathway by inducing mitophagy, leading to cardiomyocyte injury. Conclusions: Increased ROS under H/R conditions triggered cardiomyocyte injury by inducing mitophagy to suppress the ferroptosis-related SLC7A11/GSH/GPX4 signaling pathway activation. [ABSTRACT FROM AUTHOR]

Ischemic heart disease is the most prevalent cause of death worldwide affecting both the gender of all age groups. The high mortality rate is due to damage of myocardial tissue that emanates at the time of myocardial ischemia and re-oxygenation, thus averting reperfusion injury is recognized as a potential way to reduce acute cardiac injury and subsequent mortality. Flavonoids are polyphenol derivatives of plant origin and empirical shreds of evidence substantiate their numerous activities such as antioxidant, anti-inflammatory, anti-apoptotic, and anti-thrombotic activity, leading to their role in cardio protection. Recent investigations have unveiled the capacity of flavonoids to impede pivotal regulatory enzymes, signaling molecules, and transcription factors that orchestrate the mediators participating in the inflammatory cascade. The present comprehensive review, dwells on the preclinical studies on the effectiveness of flavonoids from the year 2007 to 2023, for the prevention and therapeutics for myocardial ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect and mechanism of the activation of nuclear factor κB (NF-κB) on myocardial ischemia-reperfusion (IR) injury under hyperglycemic condition. Methods Forty-eight male C57BL/6J mice were acclimated for one week and were randomly assigned into six groups： non-diabetic sham-operated group (NG-Sham group), non-diabetic ischemia-reperfusion group (NG-IR group), diabetic sham-operated group (DM-Sham group), diabetic ischemia-reperfusion group (DM-IR group), diabetic ischemia-reperfusion negative control group (DM-IR-NC group), and diabetic ischemia-reperfusion NF- κB recombinant protein intervention group (DM-IR-NF- κB group), with eight mice in each group. Mice in the NG-Sham and NG-IR groups were fed the normal diet. Mice in the NG-IR group underwent myocardial infarction (MI) modeling by ligation of the left anterior descending (LAD) coronary artery, while mice in the NG-Sham group had the LAD artery exposed but not ligated. Mice in the DM-IR group received intraperi‑ toneal injections of streptozotocin (STZ) at 40 mg/kg for four consecutive days to induce diabetes mellitus (DM) . One week after the establishment of the DM model, MI was induced by LAD ligation. Mice in the DM-Sham group underwent the same procedure for DM induction and had the LAD artery exposed but not ligated. Mice in the DM-IR-NF-κB and DM-IR-NC groups underwent the same DM induction procedure and MI modeling. Mice in the DM-IR-NF- κB group received an intravenous injection of NF-κB recombinant protein at 0. 5 mg/kg via the tail vein 30 minutes before chest opening, while mice in the DM-IR-NC group did not receive the NF-κB recombinant protein. The myocardial infarct area in the NG-IR and DM-IR groups was assessed by TTC staining. The mRNA expression levels of NF-κB, IL-6, IL-1β, and TNF-α in the myocardial tissues were measured by RT-qPCR. The mitochondrial membrane potential in the NG-Sham, NG-IR, DM-Sham, and DM-IR groups was evaluated using JC-1 staining, and mitochondrial reactive oxygen species (ROS) content was assessed using MitoSOX staining. AMPK and p-AMPK protein expression levels in the myocardial tis‑ sues were determined by Western blotting. Serum AST and LDH activities in the DM-IR-NC and DM-IR-NF-κB groups were measured by colorimetric assays, and the content of serum CK-MB was determined using double-antibody sandwich ELISA. Results Compared with the NG-IR group, the myocardial infarct area increased (P<0. 05) and the mRNA expression of NF-κB in the myocardial tissues was up-regulated (P<0. 05), while the mRNA expression levels of IL-6, IL-1β, and TNF- α did not show significant changes in the DM-IR group (all P>0. 05) . Compared with the NG-Sham group, the NG-IR and DM-Sham groups exhibited decreased mitochondrial membrane potential and increased ROS content (both P<0. 05) ； compared with the NG-IR group, the DM-IR group showed further decreased mitochondrial membrane potential and increased ROS content (both P<0. 05) . Pearson correlation analysis showed that there was a significant posi‑ tive correlation between the NF-κB mRNA level and mitochondrial membrane potential in the myocardial tissues of IR mice (r=0. 496, P<0. 05) . Compared with the NG-IR group, the DM-IR group exhibited up-regulated AMPK protein expres‑ sion, down-regulated p-AMPK protein expression, and decreased p-AMPK/AMPK ratio (all P<0. 05) . Compared with the DM-IR-NC group, the content of serum AST, LDH, and CK-MB increased (all P<0. 05), the relative expression levels of p-AMPK protein and p-AMPK/AMPK in the myocardial tissues decreased (all P<0. 05), while the relative expression of AMPK protein did not change significantly in the DM-IR-NF-κB group (P>0. 05) . Conclusion The activation of NF-κB can promote the susceptibility of the myocardium to IR injury under hyperglycemic condition, and the mechanism may be that NF-κB induces the inactivation of the AMPK signaling pathway and disorder of mitochondrial quality control. [ABSTRACT FROM AUTHOR]

Objective: As the most common metabolic disease, diabetes is closely related to cardiovascular disease and is an independent risk factor for the occurrence of acute myocardial infarction. Nuclear factor erythroid-2-related factor 2 (NRF2) is a key regulator of the cellular antioxidant response, which increases the transcription of downstream antioxidant genes by interacting with other proteins and binding to antioxidant response elements, thereby maintaining the dynamic balance of redox states. Some studies have shown that NRF2 is involved in the regulation of the occurrence and development of diabetic myocardial ischemia - reperfusion injury, but its mechanism is not yet fully understood. This paper mainly reviews the research progress of NRF2 signaling pathway related to diabetic myocardial ischemia - reperfusion injury and NRF2 targeted therapies, providing new insights for the clinical treatment of diabetic myocardial ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Purpose: Myocardial ischemia-reperfusion injury (MIRI) is characterized by inflammation and ferroptosis, but the precise mechanisms remain unknown. This study used single-cell transcriptomics technology to investigate the changes in various cell subtypes during MIRI and the regulatory network of ferroptosis-related genes and immune infiltration. Methods: Datasets GSE146285, GSE83472, GSE61592, and GSE160516 were obtained from Gene Expression Omnibus. Each cell subtype in the tissue samples was documented. The Seurat package was used for data preprocessing, standardization, and clustering. Cellphonedb was used to investigate the ligand-receptor interactions between cells. The hdWGCNA analysis was used to create a gene co-expression network. GSVA and GSEA were combined to perform functional enrichment and pathway analysis on the gene set. Furthermore, characteristic genes of the disease were identified using Lasso regression and SVM algorithms. Immune cell infiltration analysis was also performed. MIRI rat models were created, and samples were taken for RT-qPCR and Western blot validation. Results: The proportion of MIRI samples in the C2, C6, and C11 subtypes was significantly higher than that of control samples. Three genes associated with ferroptosis (CD44, Cfl1, and Zfp36) were identified as MIRI core genes. The expression of these core genes was significantly correlated with mast cells and monocyte immune infiltrating cells. The experimental validation confirmed the upregulation of Cd44 and Zfp36 expression levels in MIRI, consistent with current study trends. Conclusion: This study used single-cell transcriptomics technology to investigate the molecular mechanisms underpinning MIRI. Numerous important cell subtypes, gene regulatory networks, and disease-associated immune infiltration were also discovered. These findings provide new information and potential therapeutic targets for MIRI diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Abstract Migratory cells exist in the heart, such as immune cells, fibroblasts, endothelial cells, etc. During myocardium injury, such as ischemia–reperfusion (MIRI), cells migrate to the site of injury to perform repair functions. However, excessive aggregation of these cells may exacerbate damage to the structure and function of the heart, such as acute myocarditis and myocardial fibrosis. Myocardial injury releases exosomes, which are a type of vesicle with signal transduction function and the miRNA carried by exosomes can control cell migration function. Therefore, regulating this migratory cell population through cardiac-derived exosomal miRNA is crucial for protecting and maintaining cardiac function. Through whole transcriptome RNA sequencing, exosomal miRNA sequencing and single-cell dataset analysis, we (1) determined the potential molecular regulatory role of the lncRNA‒miRNA‒mRNA axis in MIRI, (2) screened four important exosomal miRNAs that could be released by cardiac tissue, and (3) screened seven genes related to cell locomotion that are regulated by four miRNAs, among which Tradd and Ephb6 may be specific for promoting migration of different cells of myocardial tissue in myocardial infarct. We generated a core miRNA‒mRNA network based on the functions of the target genes, which may be not only a target for cardiac repair but also a potential diagnostic marker for interactions between the heart and other tissues or organs. In conclusion, we elucidated the potential mechanism of MIRI in cardiac remodeling from the perspective of cell migration, and inhibition of cellular overmigration based on this network may provide new therapeutic targets for MIRI and to prevent MIRI from developing into other diseases.

Abstract Background Myocardial ischemia-reperfusion injury (MI/RI) is an unavoidable risk event for acute myocardial infarction, with ferroptosis showing close involvement. We investigated the mechanism of MI/RI inducing myocardial injury by inhibiting the ferroptosis-related SLC7A11/glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathway and activating mitophagy. Methods A rat MI/RI model was established, with myocardial infarction area and injury assessed by TTC and H&E staining. Rat cardiomyocytes H9C2 were cultured in vitro, followed by hypoxia/reoxygenation (H/R) modeling and the ferroptosis inhibitor lipoxstatin-1 (Lip-1) treatment, or 3-Methyladenine or rapamycin treatment and overexpression plasmid (oe-SLC7A11) transfection during modeling. Cell viability and death were evaluated by CCK-8 and LDH assays. Mitochondrial morphology was observed by transmission electron microscopy. Mitochondrial membrane potential was detected by fluorescence dye JC-1. Levels of inflammatory factors, reactive oxygen species (ROS), Fe2+, malondialdehyde, lipid peroxidation, GPX4 enzyme activity, glutathione reductase, GSH and glutathione disulfide, and SLC7A11, GPX4, LC3II/I and p62 proteins were determined by ELISA kit, related indicator detection kits and Western blot. Results The ferroptosis-related SLC7A11/GSH/GPX4 pathway was repressed in MI/RI rat myocardial tissues, inducing myocardial injury. H/R affected GSH synthesis and inhibited GPX4 enzyme activity by down-regulating SLC7A11, thus promoting ferroptosis in cardiomyocytes, which was averted by Lip-1. SLC7A11 overexpression improved H/R-induced cardiomyocyte ferroptosis via the GSH/GPX4 pathway. H/R activated mitophagy in cardiomyocytes. Mitophagy inhibition reversed H/R-induced cellular ferroptosis. Mitophagy activation partially averted SLC7A11 overexpression-improved H/R-induced cardiomyocyte ferroptosis. H/R suppressed the ferroptosis-related SLC7A11/GSH/GPX4 pathway by inducing mitophagy, leading to cardiomyocyte injury. Conclusions Increased ROS under H/R conditions triggered cardiomyocyte injury by inducing mitophagy to suppress the ferroptosis-related SLC7A11/GSH/GPX4 signaling pathway activation.

Abstract Objective We aim to investigate the association between prognosis and outcomes following myocardial ischemia-reperfusion injury, as well as peripheral blood levels of NLRP3 and the triglyceride-glucose index (TyG). Methods A total of 100 patients who underwent emergency coronary intervention following myocardial infarction confirmed by coronary angiography at our hospital between October 2021 and May 2023 were included in this study. Patients were stratified into two groups based on their prognoses: the control group (n = 73), which did not experience new myocardial infarctions or require hospitalization for heart failure or suffer sudden cardiac death post-interventional treatment; and the observation group (n = 27), which experienced one or more cardiovascular events post-treatment. Patient demographics were obtained from clinical records while biochemical analyses assessed peripheral blood triglycerides, blood glucose levels, and TyG index. Additionally, ELISA measurements determined levels of NLRP3 as well as inflammatory factors IL-6, TNF-α, and CRP in peripheral blood samples. Cardiac function was evaluated according to NYHA standards. Univariable Cox regression analysis identified factors influencing patient prognosis while Pearson correlation analysis examined relationships among prognosis, outcomes following myocardial ischemia-reperfusion injury, TyG index, and peripheral blood NLRP3. Results No significant differences were observed in the general characteristics between the two patient groups (P > 0.05). However, the observation group exhibited higher levels of peripheral blood triglycerides, blood glucose, and TyG index compared to the control group (P

Abstract Ischemic heart disease is the most prevalent cause of death worldwide affecting both the gender of all age groups. The high mortality rate is due to damage of myocardial tissue that emanates at the time of myocardial ischemia and re-oxygenation, thus averting reperfusion injury is recognized as a potential way to reduce acute cardiac injury and subsequent mortality. Flavonoids are polyphenol derivatives of plant origin and empirical shreds of evidence substantiate their numerous activities such as antioxidant, anti-inflammatory, anti-apoptotic, and anti-thrombotic activity, leading to their role in cardio protection. Recent investigations have unveiled the capacity of flavonoids to impede pivotal regulatory enzymes, signaling molecules, and transcription factors that orchestrate the mediators participating in the inflammatory cascade. The present comprehensive review, dwells on the preclinical studies on the effectiveness of flavonoids from the year 2007 to 2023, for the prevention and therapeutics for myocardial ischemia-reperfusion injury. Graphical Abstract

Abstract Reperfusion therapy is critical for saving heart muscle after myocardial infarction, but the process of restoring blood flow can itself exacerbate injury to the myocardium. This phenomenon is known as myocardial ischemia-reperfusion injury (MIRI), which includes oxidative stress, inflammation, and further cell death. microRNA-146a (miR-146a) is known to play a significant role in regulating the immune response and inflammation, and has been studied for its potential impact on the improvement of heart function after myocardial injury. However, the delivery of miR-146a to the heart in a specific and efficient manner remains a challenge as extracellular RNAs are unstable and rapidly degraded. Milk exosomes (MEs) have been proposed as ideal delivery platform for miRNA-based therapy as they can protect miRNAs from RNase degradation. In this study, the effects of miR-146a containing MEs (MEs-miR-146a) on improvement of cardiac function were examined in a rat model of MIRI. To enhance the targeting delivery of MEs-miR-146a to the site of myocardial injury, the ischemic myocardium-targeted peptide IMTP was modified onto the surfaces, and whether the modified MEs-miR-146a could exert a better therapeutic role was examined by echocardiography, myocardial injury indicators and the levels of inflammatory factors. Furthermore, the expressions of miR-146a mediated NF-κB signaling pathway-related proteins were detected by western blotting and qRT-PCR to further elucidate its mechanisms. MiR-146 mimics were successfully loaded into the MEs by electroporation at a square wave 1000 V voltage and 0.1 ms pulse duration. MEs-miR-146a can be up-taken by cardiomyocytes and protected the cells from oxygen glucose deprivation/reperfusion induced damage in vitro. Oral administration of MEs-miR-146a decreased myocardial tissue apoptosis and the expression of inflammatory factors and improved cardiac function after MIRI. The miR-146a level in myocardium tissues was significantly increased after the administration IMTP modified MEs-miR-146a, which was higher than that of the MEs-miR-146a group. In addition, intravenous injection of IMTP modified MEs-miR-146a enhanced the targeting to heart, improved cardiac function, reduced myocardial tissue apoptosis and suppressed inflammation after MIRI, which was more effective than the MEs-miR-146a treatment. Moreover, IMTP modified MEs-miR-146a reduced the protein levels of IRAK1, TRAF6 and p-p65. Therefore, IMTP modified MEs-miR-146a exerted their anti-inflammatory effect by inhibiting the IRAK1/TRAF6/NF-κB signaling pathway. Taken together, our findings suggested miR-146a containing MEs may be a promising strategy for the treatment of MIRI with better outcome after modification with ischemic myocardium-targeted peptide, which was expected to be applied in clinical practice in future.

At present, the incidence rate of acute myocardial infarction is increasing year by year. Patients with acute myocardial infarction may experience myocardial ischemia-reperfusion injury (MIRI) after reperfusion of coronary blood flow, which further exacerbates the injury and leads to a decrease in the patient' s quality of life. Therefore, reducing MIRI has become one of the urgent issues that need to be addressed in the treatment of cardiovascular diseases. Traditional Chinese medicine has the advantages of multiple pathways and targets in the treatment of MIRI, which can provide new ideas for alleviating MIRI. The Wnt signaling pathway is closely related to the occurrence and development of MIRI, and it can improve MIRI by regulating inflammatory response, cell apoptosis, oxidative stress, autophagy, and other factors. The article reviews the research progress of traditional Chinese medicine in alleviating MIRI by regulating the Wnt signaling pathway, in order to provide a theoretical basis for the treatment of MIRI. [ABSTRACT FROM AUTHOR]

Exercise improves cardiac function and metabolism. Although long-term exercise leads to circulating and micro-environmental metabolic changes, the effect of exercise on protein post-translational lactylation modifications as well as its functional relevance is unclear. Here, we report that lactate can regulate cardiomyocyte changes by improving protein lactylation levels and elevating intracellular N6-methyladenosine RNA-binding protein YTHDF2. The intrinsic disorder region of YTHDF2 but not the RNA m6A-binding activity is indispensable for its regulatory function in influencing cardiomyocyte cell size changes and oxygen glucose deprivation/re-oxygenation (OGD/R)-stimulated apoptosis via upregulating Ras GTPase-activating protein-binding protein 1 (G3BP1). Downregulation of YTHDF2 is required for exercise-induced physiological cardiac hypertrophy. Moreover, myocardial YTHDF2 inhibition alleviated ischemia/reperfusion-induced acute injury and pathological remodeling. Our results here link lactate and lactylation modifications with RNA m6A reader YTHDF2 and highlight the physiological importance of this innovative post-transcriptional intrinsic regulation mechanism of cardiomyocyte responses to exercise. Decreasing lactylation or inhibiting YTHDF2/G3BP1 might represent a promising therapeutic strategy for cardiac diseases. [ABSTRACT FROM AUTHOR]

AIM: The effect of salvianolic acid B on myocardial ischemia-reperfusion injury (MIRI) and its possible mechanism of action. METHODS: In this experiment, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to establish a myocardial injury model by hypoxia for 6 hours and reoxygenation for 24 hours. Salvianolic acid B (7. 5, 15, 30, 60, 120 μg/mL) was selected Study the effects of 5 dose groups on the impedance and field potential of hiPSC-CMs and hiPSC-CMs myocardial injury models. Subsequently, animal experiments were conducted and divided into sham surgery group, myocardial ischemia-reperfusion model group, salvianolic acid B low (15 mg/kg), medium (30 mg/kg), high (60 mg/kg) dose group, and positive control propranolol (2. 5 mg/kg) group. After 4 days of gastric administration, left anterior descending coronary artery ligation surgery (ischemia for 30 minutes, reperfusion for 24 hours) was performed to establish a rat MIRI model, and the ischemic area of the rat heart was observed using TTC staining method. HE staining method was used to observe the pathological morphology of rat myocardial structure. Exploring the protective effect of salvianolic acid B on MIRI by measuring serum central muscle enzyme activity using a fully automated biochemical analyzer. Use a reagent kit to detect the possible antioxidant mechanisms involved in the protection of MIRI by salvianolic acid B. RESULTS: Salvianolic acid B has the effect of enhancing the contractility of hiPSC CMs, reducing myocardial injury, and improving field potential function. And it can effectively reduce the myocardial ischemic area of the rat MIRI model, improve myocardial structural damage, reduce myocardial enzyme activity, and protect the heart. In addition, it can also reduce the content of malondialdehyde (MDA) in the serum of MIRI rats, enhance the activity of superoxide dismutase (SOD) and reduced glutathione (GSH), and play an antioxidant role in improving myocardial injury. CONCLUSION: Salvianolic acid B can effectively reduce MIRI and play a role in improving the physiological function of myocardial cells and protecting the heart. Its mechanism of action may be related to reducing MDA levels, increasing SOD activity, and enhancing GSH activity of the serum [ABSTRACT FROM AUTHOR]

Background: Myocardial ischemia–reperfusion injury (MIRI) refers to severe damage to the ischemic myocardium following the restoration of blood flow, and it is a major complication of reperfusion therapy for myocardial infarction. Notably, drugs such as metoprolol have been utilized to reduce ischemia–reperfusion injury. Tanshinone IIA is a major constituent extracted from Salvia miltiorrhiza Bunge. Recently, tanshinone IIA has been studied extensively in animal models for controlling MIRI. Therefore, we conducted a meta-analysis on the application of tanshinone IIA in rat models with MIRI to evaluate the therapeutic effects of tanshinone IIA. Methods: A comprehensive search was conducted across PubMed, Web of Science, Embase, the Cochrane Library, the China National Knowledge Infrastructure database, the Wanfang database, and the Chinese Scientific Journal Database to gather studies on tanshinone IIA intervention in rat models with MIRI.We employed SYRCLE's risk of bias tool to assess study quality. The primary outcome indicators were superoxide dismutase (SOD) and malondialdehyde (MDA). Myocardial infarction area was a secondary outcome indicator. This study was registered at PROSPERO (registration number CRD 42022344447). Results: According to the inclusion and exclusion criteria, 15 eligible studies were selected from 295 initially identified studies. In rat models with MIRI, tanshinone IIA significantly increased SOD levels while reducing MDA levels and myocardial infarction area. Moreover, the duration of myocardial ischemia influenced the effectiveness of tanshinone IIA. However, additional high-quality research studies are needed to establish the efficacy and definitive guidelines for the use of tanshinone IIA. Animal studies demonstrated that tanshinone IIA exerted a significant therapeutic effect when the ischemia duration was less than 40 minutes. Tanshinone IIA was found to be more effective when administered via intravenous, intraperitoneal, and intragastric routes at doses above 5 mg/kg. Additionally, treatment with tanshinone IIA at all stages—prior to myocardial ischemia, after ischemia but before reperfusion, prior to ischemia and after reperfusion, and after reperfusion—showed satisfactory results. Conclusions: Tanshinone IIA enhanced SOD activity and reduced MDA levels, thereby ameliorating oxidative stress damage during MIRI. Additionally, it reduced the myocardial infarction area, indicating its effectiveness in mitigating MIRI-induced damage in rats and demonstrating a myocardial protective effect. These findings contribute valuable insights for developing MIRI treatment strategies. [ABSTRACT FROM AUTHOR]

Myocardial ischemia‐reperfusion injury (MIRI) represents a critical pathology in acute myocardial infarction (AMI), which is characterized by high mortality and morbidity. Cardiac microvascular dysfunction contributes to MIRI, potentially culminating in heart failure (HF). Pigment epithelium‐derived factor (PEDF), which belongs to the non‐inhibitory serpin family, exhibits several physiological effects, including anti‐angiogenesis, anti‐inflammatory and antioxidant properties. Our study aims to explore the impact of PEDF and its functional peptide 34‐mer on both cardiac microvascular perfusion in MIRI rats and human cardiac microvascular endothelial cells (HCMECs) injury under hypoxia reoxygenation (HR). It has been shown that MIRI is accompanied by ferroptosis in HCMECs. Furthermore, we investigated the effect of PEDF and its 34‐mer, particularly regarding the Nrf2/HO‐1 signalling pathway. Our results demonstrated that PEDF 34‐mer significantly ameliorated cardiac microvascular dysfunction following MIRI. Additionally, they exhibited a notable suppression of ferroptosis in HCMECs, and these effects were mediated through activation of Nrf2/HO‐1 signalling. These findings highlight the therapeutic potential of PEDF and 34‐mer in alleviating microvascular dysfunction and MIRI. By enhancing cardiac microvascular perfusion and mitigating endothelial ferroptosis, PEDF and its derivative peptide represent promising candidates for the treatment of AMI. [ABSTRACT FROM AUTHOR]

Reperfusion therapy is critical for saving heart muscle after myocardial infarction, but the process of restoring blood flow can itself exacerbate injury to the myocardium. This phenomenon is known as myocardial ischemia-reperfusion injury (MIRI), which includes oxidative stress, inflammation, and further cell death. microRNA-146a (miR-146a) is known to play a significant role in regulating the immune response and inflammation, and has been studied for its potential impact on the improvement of heart function after myocardial injury. However, the delivery of miR-146a to the heart in a specific and efficient manner remains a challenge as extracellular RNAs are unstable and rapidly degraded. Milk exosomes (MEs) have been proposed as ideal delivery platform for miRNA-based therapy as they can protect miRNAs from RNase degradation. In this study, the effects of miR-146a containing MEs (MEs-miR-146a) on improvement of cardiac function were examined in a rat model of MIRI. To enhance the targeting delivery of MEs-miR-146a to the site of myocardial injury, the ischemic myocardium-targeted peptide IMTP was modified onto the surfaces, and whether the modified MEs-miR-146a could exert a better therapeutic role was examined by echocardiography, myocardial injury indicators and the levels of inflammatory factors. Furthermore, the expressions of miR-146a mediated NF-κB signaling pathway-related proteins were detected by western blotting and qRT-PCR to further elucidate its mechanisms. MiR-146 mimics were successfully loaded into the MEs by electroporation at a square wave 1000 V voltage and 0.1 ms pulse duration. MEs-miR-146a can be up-taken by cardiomyocytes and protected the cells from oxygen glucose deprivation/reperfusion induced damage in vitro. Oral administration of MEs-miR-146a decreased myocardial tissue apoptosis and the expression of inflammatory factors and improved cardiac function after MIRI. The miR-146a level in myocardium tissues was significantly increased after the administration IMTP modified MEs-miR-146a, which was higher than that of the MEs-miR-146a group. In addition, intravenous injection of IMTP modified MEs-miR-146a enhanced the targeting to heart, improved cardiac function, reduced myocardial tissue apoptosis and suppressed inflammation after MIRI, which was more effective than the MEs-miR-146a treatment. Moreover, IMTP modified MEs-miR-146a reduced the protein levels of IRAK1, TRAF6 and p-p65. Therefore, IMTP modified MEs-miR-146a exerted their anti-inflammatory effect by inhibiting the IRAK1/TRAF6/NF-κB signaling pathway. Taken together, our findings suggested miR-146a containing MEs may be a promising strategy for the treatment of MIRI with better outcome after modification with ischemic myocardium-targeted peptide, which was expected to be applied in clinical practice in future. [ABSTRACT FROM AUTHOR]

Background: Myocardial ischemia-reperfusion injury (I/R) has been improved with drugs and effective reperfusion, but it still cannot be prevented. Methods: To investigate whether renal denervation (RDN) reduces cardiomyocyte apoptosis by ameliorating endoplasmic reticulum stress, 60 male specific pathogen-free (SPF) Wistar rats were randomly divided into 6 groups (n = 6). We established the I/R rat model by ligating the left anterior descending artery. The I/R+ angiotensin receptor neprilysin inhibitors (ARNI) group received ARNIs for 2 weeks until euthanasia. Results: The I/R+RDN and I/R+ARNI groups have signifiantly ameliorated left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) and reversed expansion of the left ventricular end-systolic diameter (LVSD) and left ventricular end diastolic diameter (LVDD) compared to the I/R group. The levels of norepinephrine (NE), angiotensin II, and aldosterone (ALD) increased signifiantly in the I/R group, but decreased signifiantly after RDN and ARNI intervention. In the I/R+RDN and I/R+ARNI groups, the myocardial tissue edema was alleviated. The infarct size was smaller in the I/R+RDN and I/R+ARNI groups compared to the I/R group. Apoptosis of cardiomyocytes and fib oblasts in myocardial tissue increased signifiantly in the I/R group, which was greatly diminished by RDN and ARNI. The expression of Bax, caspase-3, CHOP, PERK, and ATF4 protein was signifiantly increased in the I/R group, which compared to other groups, and the level of CHOP, PERK, and ATF4 gene expression increased. After RDN intervention, these expression levels recovered to varying degrees. Conclusion: The effect of RDN may be associated with regulating the endoplasmic reticulum stress PERK/ATF4 signaling pathway. [ABSTRACT FROM AUTHOR]

This research is concentrated on investigating the role and mechanism of miR-652-3p in the protective effects of isoflurane (ISO) against myocardial ischemia–reperfusion (I/R) injury. H9c2 cells underwent pretreatment with varying concentrations of ISO, and subsequently, a hypoxia/reoxygenation (H/R) model was constructed. The levels of miR-652-3p, ISL LIM homeobox 1 (ISL1), and inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) were evaluated through reverse transcription polymerase chain reaction (RT-qPCR). Enzyme-linked immunosorbent assay was employed to investigate concentrations of myocardial injury markers, such as creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI). Cell counting kit-8 was used to evaluate cell viability, while flow cytometry was utilized to measure apoptosis. Additionally, a dual luciferase reporter assay was conducted to validate the targeting relationship between ISL1 and miR-652-3p. Herein, we confirmed that the level of miR-652-3p was gradually increased with prolonged hypoxia; nevertheless, this increase was suppressed by ISO pretreatment (P < 0.05). Additionally, ISO pretreatment prevented the decrease in cell viability, increase in apoptosis, and overproduction of IL-6, TNF-α, CK-MB, and cTnI induced by H/R (P < 0.05). However, the inhibitory effects of ISO were counteracted by the increased levels of miR-652-3p (P < 0.05). ISL1 is a potential target of miR-652-3p. H/R induction suppressed ISL1 levels compared to the control, but ISO treatment increased its expression (P < 0.05). Overexpression of ISL1 inhibited the elimination of the protective effect of ISO on myocardial damage induced by the elevation of miR-652-3p (P < 0.05). The findings of this research confirm that miR-652-3p attenuated the protective effect of ISO on cardiomyocytes in myocardial ischemia by targeting ISL1. [ABSTRACT FROM AUTHOR]

Objective: To investigate the potential role of Tongxinluo (TXL) in attenuating myocardial fibrosis after myocardial ischemia-reperfusion injury (MIRI) in mice. Methods: A MIRI mouse model was established by left anterior descending coronary artery ligation for 45 min. According to a random number table, 66 mice were randomly divided into 6 groups (n=11 per group): the sham group, the model group, the LY-294002 group, the TXL group, the TXL+LY-294002 group and the benazepril (BNPL) group. The day after modeling, TXL and BNPL were administered by gavage. Intraperitoneal injection of LY-294002 was performed twice a week for 4 consecutive weeks. Echocardiography was used to measure cardiac function in mice. Masson staining was used to evaluate the degree of myocardial fibrosis in mice. Qualitative and quantitative analysis of endothelial mesenchymal transition (EndMT) after MIRI was performed by immunohistochemistry, immunofluorescence staining and flow cytometry, respectively. The protein expressions of platelet endothelial cell adhesion molecule-1 (CD31), α-smoth muscle actin (α-SMA), phosphatidylinositol-3-kinase (PI3K) and phospho protein kinase B (p-AKT) were assessed using Western blot. Results: TXL improved cardiac function in MIRI mice, reduced the degree of myocardial fibrosis, increased the expression of CD31 and inhibited the expression of α-SMA, thus inhibited the occurrence of EndMT (P<0.05 or P<0.01). TXL significantly increased the protein expressions of PI3K and p-AKT (P<0.05 or P<0.01). There was no significant difference between TXL and BNPL group (P>0.05). In addition, the use of the PI3K/AKT pathway-specific inhibitor LY-294002 to block this pathway and combination with TXL intervention, eliminated the protective effect of TXL, further supporting the protective effect of TXL. Conclusion: TXL activated the PI3K/AKT signaling pathway to inhibit EndMT and attenuated myocardial fibrosis after MIRI in mice. [ABSTRACT FROM AUTHOR]

Ischemic heart disease, associated with high morbidity and mortality, represents a major challenge for the development of drug-based strategies to improve its prognosis. Results of pre-clinical studies suggest that agonists of cannabinoid CB2 receptors and multitarget cannabidiol might be potential cardioprotective strategies against ischemia-reperfusion injury. The aim of our study was to reevaluate the cardioprotective effects of cannabinoids against ischemiareperfusion injury according to the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria published recently by the European Union (EU) CARDIOPROTECTION COST ACTION. To meet the minimum criteria of those guidelines, experiments should be performed (i) on healthy small animals subjected to ischemia with reperfusion lasting for at least 2 hours and (ii) confirmed in small animals with comorbidities and comedications and (iii) in large animals. Our analysis revealed that the publications regarding cardioprotective effects of CB2 receptor agonists and cannabidiol did not meet all three strict steps of IMPACT. Thus, additional experiments are needed to confirm the cardioprotective activities of (endo) cannabinoids mainly on small animals with comorbidities and on large animals. Moreover, our publication underlines the significance of the IMPACT criteria for a proper planning of preclinical experiments regarding cardiac ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Previous research has identified intravascular platelet thrombi in regions affected by myocardial ischemia-reperfusion (MI/R) injury and neighbouring areas. However, the occurrence of arterial thrombosis in the context of MI/R injury remains unexplored. This study utilizes intravital microscopy to investigate carotid artery thrombosis during MI/R injury in rats, establishing a connection with the presence of prothrombotic cellular fibronectin containing extra domain A (CFN-EDA) protein. Additionally, the study examines samples from patients with coronary artery disease (CAD) both before and after coronary artery bypass grafting (CABG). Levels of CFN-EDA significantly increase following MI with further elevation observed following reperfusion of the ischemic myocardium. Thrombotic events, such as thrombus formation and growth, show a significant increase, while the time to complete cessation of blood flow in the carotid artery significantly decreases following MI/R injury induced by ferric chloride. The acute infusion of purified CFN-EDA protein accelerates in-vivo thrombotic events in healthy rats and significantly enhances in-vitro adenosine diphosphate and collagen-induced platelet aggregation. Treatment with anti-CFN-EDA antibodies protected the rat against MI/R injury and significantly improved cardiac function as evidenced by increased end-systolic pressure-volume relationship slope and preload recruitable stroke work compared to control. Similarly, in a human study, plasma CFN-EDA levels were notably elevated in CAD patients undergoing CABG. Post-surgery, these levels continued to rise over time, alongside cardiac injury biomarkers such as cardiac troponin and B-type natriuretic peptide. The study highlights that increased CFN-EDA due to CAD or MI initiates a destructive positive feedback loop by amplifying arterial thrombus formation, potentially exacerbating MI/R injury. [Display omitted] • The study emphasizes a direct and robust connection between arterial thrombosis and MI/R injury, previously unidentified. • Increased CFN-EDA levels post-CAD or MI injury potentially accelerate arterial thrombosis events in reperfusion injury. • The significant increase in CFN-EDA following CABG, along with elevated cardiac-injury biomarkers, underscores its clinical significance. • Targeting CFN-EDA before treatment may offer promising strategy to alleviate the hastened thrombotic events linked to MI/R injury. [ABSTRACT FROM AUTHOR]

Objective: Panax quinquefolius saponins (PQS) and Panax notoginseng saponins (PNS) are key bioactive compounds in Panax quinquefolius L. and Panax notoginseng, commonly used in the treatment of clinical ischemic heart disease. However, their potential in mitigating myocardial ischemia-reperfusion injury remains uncertain. This study aims to evaluate the protective effects of combined PQS and PNS administration in myocardial hypoxia/reoxygenation (H/R) injury and explore the underlying mechanisms. Methods: To investigate the involvement of HIF-1α/BNIP3 mitophagy pathway in the myocardial protection conferred by PNS and PQS, we employed small interfering BNIP3 (siBNIP3) to silence key proteins of the pathway. H9C2 cells were categorized into four groups: control, H/R, H/R + PQS + PNS, and H/R + PQS + PNS+siBNIP3. Cell viability was assessed by Cell Counting Kit-8, apoptosis rates determined via flow cytometry, mitochondrial membrane potential assessed with the JC-1 fluorescent probes, intracellular reactive oxygen species detected with 2′,7′-dichlorodihydrofluorescein diacetate, mitochondrial superoxide production quantified with MitoSOX Red, and autophagic flux monitored with mRFP-GFP-LC3 adenoviral vectors. Autophagosomes and their ultrastructure were visualized through transmission electron microscopy. Moreover, mRNA and protein levels were analyzed via real-time PCR and Western blotting. Results: PQS + PNS administration significantly increased cell viability, reduced apoptosis, lowered reactive oxygen species levels and mitochondrial superoxide production, mitigated mitochondrial dysfunction, and induced autophagic flux. Notably, siBNIP3 intervention did not counteract the cardioprotective effect of PQS + PNS. The PQS + PNS group showed downregulated mRNA expression of HIF-1α and BNIP3, along with reduced HIF-1α protein expression compared to the H/R group. Conclusions: PQS + PNS protects against myocardial H/R injury, potentially by downregulating mitophagy through the HIF-1α/BNIP3 pathway. [ABSTRACT FROM AUTHOR]

Acute heart attack is the primary cause of cardiovascular-related death worldwide. A common treatment is reperfusion of ischemic tissue, which can cause irreversible damage to the myocardium. The number of mitochondria in cardiomyocytes is large, which generate adenosine triphosphate (ATP) to sustain proper cardiac contractile function, and mitochondrial dysfunction plays a crucial role in cell death during myocardial ischemia-reperfusion, leading to an increasing number of studies investigating the impact of mitochondria on ischemia-reperfusion injury. The disarray of mitochondrial dynamics, excessive Ca2+ accumulation, activation of mitochondrial permeable transition pores, swelling of mitochondria, ultimately the death of cardiomyocyte are the consequences of ischemia-reperfusion injury. κ-opioid receptors can alleviate mitochondrial dysfunction, regulate mitochondrial dynamics, mitigate myocardial ischemia-reperfusion injury, exert protective effects on myocardium. The mechanism of κ-OR activation during myocardial ischemia-reperfusion to regulate mitochondrial dynamics and reduce myocardial ischemia-reperfusion injury will be discussed, so as to provide theoretical basis for the protection of ischemic myocardium. [ABSTRACT FROM AUTHOR]

Oxidative stress and apoptosis play crucial roles in myocardial ischemia‒reperfusion injury (MIRI). In this study, we investigated the role of circ_0073932 in MIRI as well as its molecular mechanism. A hypoxia/reoxygenation (H/R) cardiomyocyte model was established with H9C2 cardiomyocytes, and RT–qPCR was used to measure gene expression. We observed that circ_0073932 expression was abnormally increased in the H/R cardiomyocyte model and in blood samples from MIRI patients. Inhibition of circ_0073932 suppressed H/R-induced cell apoptosis, oxidative stress (ROS, LDH and MDA), and p-JNK expression. Dual luciferase reporter assays showed that circ_0073932 targeted the downregulation of miR-493-3p, and miR-493-3p targeted the downregulation of FAF1. Furthermore, si-circ_0073932, an miR-493-3p inhibitor, oe-FAF1, or si-FAF1 were transfected into H9C2 cardiomyocytes to investigate the roles of these factors in MIRI. Our results showed that compared with the H/R group, si-circ_0073932 inhibited H/R-induced cell apoptosis, oxidative stress (ROS, LDH and MDA), and p-JNK expression. These results were reversed by the miR-493-3p inhibitor or oe-FAF1. Finally, a rat model of MIRI was established, and si-circ_0073932 was administered. Inhibition of circ_0073932 reduced the area of myocardial infarction and decreased the levels of apoptosis and oxidative stress by inhibiting the JNK signaling pathway. Our study indicated that circ_0073932 mediates MIRI via miR-493-3p/FAF1/JNK in vivo and in vitro, revealing novel insights into the pathogenesis of MIRI and providing a new target for the clinical treatment of MIRI. Suppression of circ_0073932 can inhibit myocardial apoptosis and regulate oxidative stress in MIRI through the miR-493-3p/FAF1/JNK [ABSTRACT FROM AUTHOR]

Abstract Despite the widespread adoption of emergency coronary reperfusion therapy, reperfusion‐induced myocardial injury remains a challenging issue in clinical practice. Following myocardial reperfusion, S100A8/A9 molecules are considered pivotal in initiating and regulating tissue inflammatory damage. Effectively reducing the S100A8/A9 level in ischemic myocardial tissue holds significant therapeutic value in salvaging damaged myocardium. In this study, HA (hemagglutinin)‐ and RAGE (receptor for advanced glycation end products)‐ comodified macrophage membrane‐coated siRNA nanoparticles (MMM/RNA NPs) with siRNA targeting S100A9 (S100A9‐siRNA) are successfully prepared. This nanocarrier system is able to target effectively the injured myocardium in an inflammatory environment while evading digestive damage by lysosomes. In vivo, migration of MMM/RNA NPs to myocardial injury lesions is confirmed in a myocardial ischemia‐reperfusion injury (MIRI) mouse model. Intravenous injection of MMM/RNA NPs significantly reduced S100A9 levels in serum and myocardial tissues, further decreasing myocardial infarction area and improving cardiac function. Targeted reduction of S100A8/A9 by genetically modified macrophage membrane‐coated nanoparticles may represent a new therapeutic intervention for MIRI.

Objective: Dexmedetomidine (Dex) is a potent agonist of the α2 adrenergic receptor that has been shown to possess sedative and hypnotic properties. Dex can protect against myocardial ischemia-reperfusion injury (MIRI) by inhibiting ferroptosis. However, these studies were based on Dex post-conditioning, and the role of α2 adrenergic receptors in this process is unclear. In this study, we investigated whether Dex preconditioning can prevent MIRI by attenuating ferroptosis and whether this effect depends on α2 adrenergic receptors in rats. Methods: Male Sprague–Dawley rats were randomly assigned to five groups: sham (saline-treated), I/R (ischemia-exposed), Dex + I/R (Dex pre-treatment), Dex + Yoh + I/R (Dex and yohimbine pre-treatment), and Yoh + I/R (yohimbine pre-treatment). Cardiac function, myocardial infarction, and morphological changes were assessed. Transmission electron microscopy was used to analyze mitochondrial morphology. Ferroptosis-related indicators and lipid peroxidation were measured using western blotting and qRT-PCR. Results: Our findings indicated that Dex preconditioning improved cardiac function, reduced infarct size and apoptosis, and inhibited ferroptosis in the rat myocardium after MIRI. These effects were associated with the upregulation of Nrf2, SLC7A11, and GPX4 expression, as well as the downregulation of Ferritin, TFR1, ACSL4, COX2, IL-1β, IL-6, and TNF-α expression. Importantly, yohimbine, an α2 adrenergic receptor antagonist, abolished these protective effects. Conclusion: These results suggest that Dex preconditioning can prevent MIRI by attenuating ferroptosis via α2 adrenergic receptor activation and by modulating the Nrf2/SLC7A11/GPX4 pathway.

Myocardial ischemia-reperfusion injury (MIRI) is a secondary injury caused by restoring blood flow after acute myocardial infarction, which may lead to serious arrhythmia and heart damage. In recent years, the role of potassium channels in MIRI has attracted much attention, especially the members of the two-pore domain potassium (K2P) channel family. K2P channel has unique structure and function, and the formation of its heterodimer increases its functional diversity. This paper reviews the structural characteristics, types, expression and physiological functions of K2P channel in the heart. In particular, we pay attention to whether members of the subfamily such as TWIK, TREK, TASK, TALK, THIK and TRESK participate in MIRI and their related mechanisms. Future research will help to reveal the molecular mechanism of K2P channel in MIRI and provide new strategies for the treatment of cardiovascular diseases.

Tilianin, a flavonoid compound derived from Dracocephalum moldavica L., is recognized for its diverse biological functionalities, in particular alleviating myocardial ischemia-reperfusion injury (MIRI). There is ample evidence suggesting that the NLRP3 inflammasome has a significant impact on the development of MIRI. In this study, rats undergoing the ligation and subsequent release of the left anterior descending (LAD) coronary artery and H9c2 cardiomyocytes subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) were used to investigate the effects of tilianin on NLRP3 inflammasome and its anti-MIRI mechanisms. Upon reperfusion, the rats were intraperitoneally injected with tilianin at doses of 3, 10, 30 mg/kg. H9c2 cells were treated with tilianin at concentrations of 10, 30, and 50 μg/mL. Echocardiography, TTC staining and TUNEL staining demonstrated that tilianin remarkably improved cardiac function and mitigated myocardial damage in MIRI rats. Additionally, notable inflammatory response reduction by tilianin was evidenced by subsequent hematatoxylin-eosin (HE) staining, inflammatory cytokines assay, and quantitative proteomics. Further western blotting analysis and immunofluorescence staining showed tilianin decreased the levels of TLR4, p-NF-κB, NLRP3, and ASC in MIRI rats and H9c2 cells exposed to OGD/R, alongside a significant reduction in cleaved gasdermin D, mature IL-1β and IL-18. Molecular docking, cellular thermal shift assay (CETSA) and co-immunoprecipitation (co-IP) assay revealed that tilianin impeded the interaction between NLRP3 and NEK7. Taken together, tilianin protects cardiomyocytes from MIRI by suppressing NLRP3 inflammasome through the inhibition of the TLR4/NF-κB signaling pathway and the disruption of the NEK7/NLRP3 interface. These findings underscore the potential of tilianin as a promising therapeutic candidate for MIRI.

Myocardial ischemia-reperfusion injury (MIRI) is a critical issue that arises when restoring blood flow after an ischemic event in the heart. Excessive reactive oxygen species (ROS) production during this process exacerbates cellular damage and impairs cardiac function. Recent therapeutic strategies have focused on leveraging the ROS microenvironment to design targeted drug delivery systems. ROS-responsive biomaterials have emerged as promising candidates, offering enhanced therapeutic efficacy with reduced systemic adverse effects. This review examines the mechanisms of ROS overproduction during myocardial ischemia-reperfusion and summarizes significant advancements in ROS-responsive biomaterials for MIRI treatment. We discuss various chemical strategies to impart ROS sensitivity to these materials, emphasizing ROS-induced solubility switches and degradation mechanisms. Additionally, we highlight various ROS-responsive therapeutic platforms, such as nanoparticles and hydrogels, and their unique advantages in drug delivery for MIRI. Preclinical studies demonstrating the efficacy of these materials in mitigating MIRI in animal models are reviewed, alongside their mechanisms of action and potential clinical implications. We also address the challenges and future prospects of translating these state of the art biomaterial-based therapeutics into clinical practice to improve MIRI management and cardiac outcomes. This review will provide valuable insights for researchers and clinicians working on novel therapeutic strategies for MIRI intervention.

Gastric precancerous lesion (GPL) is a crucial stage in the development of gastric cancer, characterized by incomplete intestinal epithelial chemotaxis and heterogeneous hyperplasia with high malignant potential. Early intervention in GPL is vital for preventing gastric cancer. Additionally, there are shared risk factors and pathogenesis between tumors and coronary heart disease (CHD), with an increasing number of tumor patients GPL complicated with CHD due to improved survival rates. Reperfusion therapy in CHD can result in myocardial ischemia-reperfusion injury (MIRI). Traditional Chinese medicine (TCM) has demonstrated unique advantages in treating GPL and MIRI by promoting blood circulation and removing blood stasis. Panax ginseng total saponin (PNS), a component of TCM known for its blood circulation benefits, has shown positive effects in inhibiting tumor growth and improving myocardial ischemia. This study utilized a GPL-MIRI mouse model to investigate the effects of PNS in treatment. Results indicated that PNS significantly improved typical GPL lesions in mice, such as incomplete intestinal epithelialization and heteroplasia, and also reduced myocardial infarction. At the molecular level, PNS exhibited a bidirectional regulatory role in the GPL-MIRI model. It enhanced the autophagic process in gastric mucosal cells by inhibiting the PI3K/Akt/mTOR signaling pathway, while suppressed excessive autophagy in cardiomyocytes. These findings offer new insights and treatment strategies for managing GPL and MIRI using the TCM compound PNS.

Abstract Background Diabetes is a predominant driver of coronary artery disease worldwide. This study aims to unravel the distinct characteristics of oral and gut microbiota in diabetic coronary heart disease (DCHD). Simultaneously, we aim to establish a causal link between the diabetes-driven oral-gut microbiota axis and increased susceptibility to diabetic myocardial ischemia–reperfusion injury (MIRI). Methods We comprehensively investigated the microbial landscape in the oral and gut microbiota in DCHD using a discovery cohort (n = 183) and a validation chohort (n = 68). Systematically obtained oral (tongue-coating) and fecal specimens were subjected to metagenomic sequencing and qPCR analysis, respectively, to holistically characterize the microbial consortia. Next, we induced diabetic MIRI by administering streptozotocin to C57BL/6 mice and subsequently investigated the potential mechanisms of the oral-gut microbiota axis through antibiotic pre-treatment followed by gavage with specific bacterial strains (Fusobacterium nucleatum or fecal microbiota from DCHD patients) to C57BL/6 mice. Results Specific microbial signatures such as oral Fusobacterium nucleatum and gut Lactobacillus, Eubacterium, and Roseburia faecis, were identified as potential microbial biomarkers in DCHD. We further validated that oral Fusobacterium nucleatum and gut Lactobacillus are increased in DCHD patients, with a positive correlation between the two. Experimental evidence revealed that in hyperglycemic mice, augmented Fusobacterium nucleatum levels in the oral cavity were accompanied by an imbalance in the oral-gut axis, characterized by an increased coexistence of Fusobacterium nucleatum and Lactobacillus, along with elevated cardiac miRNA-21 and a greater extent of myocardial damage indicated by TTC, HE, TUNEL staining, all of which contributed to exacerbated MIRI. Conclusion Our findings not only uncover dysregulation of the oral-gut microbiota axis in diabetes patients but also highlight the pivotal intermediary role of the increased abundance of oral F. nucleatum and gut Lactobacillus in exacerbating MIRI. Targeting the oral-gut microbiota axis emerges as a potent strategy for preventing and treating DCHD. Oral-gut microbial transmission constitutes an intermediate mechanism by which diabetes influences myocardial injury, offering new insights into preventing acute events in diabetic patients with coronary heart disease. Graphic Abstract

AbstractAcute myocardial infarction, characterized by high morbidity and mortality, has now become a serious health hazard for human beings. Conventional surgical interventions to restore blood flow can rapidly relieve acute myocardial ischemia, but the ensuing myocardial ischemia-reperfusion injury (MI/RI) and subsequent heart failure have become medical challenges that researchers have been trying to overcome. The pathogenesis of MI/RI involves several mechanisms, including overproduction of reactive oxygen species, abnormal mitochondrial function, calcium overload, and other factors that induce cell death and inflammatory responses. These mechanisms have led to the exploration of antioxidant and inflammation-modulating therapies, as well as the development of myocardial protective factors and stem cell therapies. However, the short half-life, low bioavailability, and lack of targeting of these drugs that modulate these pathological mechanisms, combined with liver and spleen sequestration and continuous washout of blood flow from myocardial sites, severely compromise the expected efficacy of clinical drugs. To address these issues, employing conventional nanocarriers and integrating them with contemporary biomimetic nanocarriers, which rely on passive targeting and active targeting through precise modifications, can effectively prolong the duration of therapeutic agents within the body, enhance their bioavailability, and augment their retention at the injured myocardium. Consequently, these approaches significantly enhance therapeutic effectiveness while minimizing toxic side effects. This article reviews current drug delivery systems used for MI/RI, aiming to offer a fresh perspective on treating this disease.

Research on ferroptosis in myocardial ischemia/reperfusion injury (MIRI) using mitochondrial viscosity as a nexus holds great promise for MIRI therapy. However, high‐precision visualisation of mitochondrial viscosity remains a formidable task owing to the debilitating electrostatic interactions caused by damaged mitochondrial membrane potential. Herein, we propose a dual‐locking mitochondria‐targeting strategy that incorporates electrostatic forces and probe‐protein molecular docking. Even in damaged mitochondria, stable and precise visualisation of mitochondrial viscosity in triggered and medicated MIRI was achieved owing to the sustained driving forces (e.g. pi‐cation, pi‐alkyl interactions, etc.) between the developed probe, CBS, and the mitochondrial membrane protein. Moreover, complemented by a western blot, we confirmed that ferrostatin‐1 exerts its therapeutic effect on MIRI by improving the system xc−/GSH/GPX4 antioxidant system, confirming the therapeutic value of ferroptosis in MIRI. This study presents a novel strategy for developing robust mitochondrial probes, thereby advancing MIRI treatment. [ABSTRACT FROM AUTHOR]

Myocardial ischemia-reperfusion injury (MIRI) is a complex process that occurs when blood flow is restored after myocardium infarction (MI) with exacerbated tissue damage. Macrophages, essential cell type of the immune response, play an important role in MIRI. Macrophage subpopulations, namely M1 and M2, are distinguished by distinct phenotypes and functions. In MIRI, macrophages infiltrate in infarcted area, shaping the inflammatory response and influencing tissue healing. Resident cardiac macrophages interact with monocyte-derived macrophages in MIRI, and influence injury progression. Key factors including chemokines, cytokines, and toll-like receptors modulate macrophage behavior in MIRI. This review aims to address recent findings on the classification and the roles of macrophages in the myocardium, spanning from MI to subsequent MIRI, and highlights various signaling pathways implicated in macrophage polarization underlining the complexity of MIRI. This article will shed light on developing advanced therapeutic strategies for MIRI management. • Modulation of macrophage polarization as a potential target for treating Myocardial Ischemia Reperfusion Injury (MIRI). • Summary for cell types of macrophages and their function. • Localization & phenotypes of macrophages in myocardial tissue. • Conclusion for recent researches of the potential mechanism of macrophages during myocardial infarction (MI) & MIRI. [ABSTRACT FROM AUTHOR]

Background: Our previous research shows that Curcumin (CUR) attenuates myocardial ischemia-reperfusion injury (MIRI) by reducing intracellular total RNA m6A levels. However, the mechanism remains unknown. Methods: For ischemia-reperfusion (IR), H9c2 cells were cultured for 6 h in serum-free low-glycemic (1 g/L) medium and a gas environment without oxygen, and then cultured for 6 h in high-glycemic (4.5 g/L) medium supplemented with 10% FBS and a 21% oxygen environment. The effects of different concentrations of CUR (5, 10, and 20 µM) treatments on signaling molecules in conventionally cultured and IR-treated H9c2 cells were examined. Results: CUR treatment significantly up-regulated the H2S levels, and the mRNA and protein expression of cystathionine γ-lyase (CSE), and down-regulated the mRNAs and proteins levels of thiosulfate sulfurtransferase (TST) and ethylmalonic encephalopathy 1 (ETHE1) in H9c2 cells conventionally cultured and subjected to IR. Exogenous H2S supply (NaHS and GYY4137) significantly reduced intracellular total RNA m6A levels, and the expression of RNA m6A "writers" METTL3 and METTL14, and increased the expression of RNA m6A "eraser" FTO in H9c2 cells conventionally cultured and subjected to IR. CSE knockdown counteracted the inhibitory effect of CUR treatment on ROS production, promotion on cell viability, and inhibition on apoptosis of H9c2 cells subjected to IR. Conclusion: CUR attenuates MIRI by regulating the expression of H2S level-regulating enzymes and increasing the endogenous H2S levels. Increased H2S levels could regulate the m6A-related proteins expression and intracellular total RNA m6A levels. [ABSTRACT FROM AUTHOR]

[Display omitted] Myocardial ischemia–reperfusion injury (MIRI) is a major hindrance to the success of cardiac reperfusion therapy. Although increased neutrophil infiltration is a hallmark of MIRI, the subtypes and alterations of neutrophils in this process remain unclear. Here, we performed single-cell sequencing of cardiac CD45+ cells isolated from the murine myocardium subjected to MIRI at six-time points. We identified diverse types of infiltrating immune cells and their dynamic changes during MIRI. Cardiac neutrophils showed the most immediate response and largest changes and featured with functionally heterogeneous subpopulations, including Ccl3hi Neu and Ym-1hi Neu, which were increased at 6 h and 1 d after reperfusion, respectively. Ym-1hi Neu selectively expressed genes with protective effects and was, therefore, identified as a novel specific type of cardiac cell in the injured heart. Further analysis indicated that neutrophils and their subtypes orchestrated subsequent immune responses in the cardiac tissues, especially instructing the response of macrophages. The abundance of Ym-1hi Neu was closely correlated with the therapeutic efficacy of MIRI when neutrophils were specifically targeted by anti-Lymphocyte antigen 6 complex locus G6D (Ly6G) or anti-Intercellular cell adhesion molecule-1 (ICAM-1) neutralizing antibodies. In addition, a neutrophil subtype with the same phenotype as Ym-1hi Neu was detected in clinical samples and correlated with prognosis. Ym-1 inhibition exacerbated myocardial injury, whereas Ym-1 supplementation significantly ameliorated injury in MIRI mice, which was attributed to the tilt of Ym-1 on the polarization of macrophages toward the repair phenotype in myocardial tissue. Overall, our findings reveal the anti-inflammatory phenotype of Ym-1hi Neu and highlight its critical role in myocardial protection during the early stages of MIRI. [ABSTRACT FROM AUTHOR]

Exosomes are multifunctional, cell-derived nanoscale membrane vesicles. Exosomes derived from certain mammalian cells have been developed as angiogenesis promoters for the treatment of myocardial ischemia–reperfusion injury, as they possess the capability to enhance endothelial cell proliferation, migration, and angiogenesis. However, the low yield of exosomes derived from mammalian cells limits their clinical applications. Therefore, we chose to extract exosome-like nanoparticles from the traditional Chinese medicine Salvia miltiorrhiza, which has been shown to promote angiogenesis. Salvia miltiorrhiza-derived exosome-like nanoparticles offer advantages, such as being economical, easily obtainable, and high-yielding, and have an ideal particle size, Zeta potential, exosome-like morphology, and stability. Salvia miltiorrhiza-derived exosome-like nanoparticles can enhance the cell viability of Human Umbilical Vein Endothelial Cells and can promote cell migration and improve the neovascularization of the cardiac tissues of myocardial ischemia–reperfusion injury, indicating their potential as angiogenesis promoters for the treatment of myocardial ischemia–reperfusion injury. [ABSTRACT FROM AUTHOR]

Myocardial ischemia–reperfusion injury (MIRI) remains a challenge in the context of reperfusion procedures for myocardial infarction (MI). While early revascularization stands as the gold standard for mitigating myocardial injury, recent insights have illuminated the paradoxical role of reperfusion, giving rise to the phenomenon known as ischemia–reperfusion injury. This comprehensive review delves into the intricate pathophysiological pathways involved in MIRI, placing a particular focus on the pivotal role of endothelium. Beyond elucidating the molecular intricacies, we explore the diverse clinical manifestations associated with MIRI, underscoring its potential to contribute substantially to the final infarct size, up to 50%. We further navigate through current preventive approaches and highlight promising emerging strategies designed to counteract the devastating effects of the phenomenon. By synthesizing current knowledge and offering a perspective on evolving preventive interventions, this review serves as a valuable resource for clinicians and researchers engaged in the dynamic field of MIRI. [ABSTRACT FROM AUTHOR]

Background and objective: Macrophages play a crucial and dichotomous role cardiac repair following myocardial ischemia-reperfusion, as they can both facilitate tissue healing and contribute to injury. This duality is intricately linked to environmental factors, and the identification of macrophage subtypes within the context of myocardial ischemia-reperfusion injury (MIRI) may offer insights for the development of more precise intervention strategies. Methods: Specific marker genes were used to identify macrophage subtypes in GSE227088 (mouse single-cell RNA sequencing dataset). Genome Set Enrichment Analysis (GSEA) was further employed to validate the identified LAM subtypes. Trajectory analysis and single-cell regulatory network inference were executed using the R packages Monocle2 and SCENIC, respectively. The conservation of LAM was verified using human ischemic cardiomyopathy heart failure samples from the GSE145154 (human single-cell RNA sequencing dataset). Fluorescent homologous double-labeling experiments were performed to determine the spatial localization of LAM-tagged gene expression in the MIRI mouse model. Results: In this study, single-cell RNA sequencing (scRNA-seq) was employed to investigate the cellular landscape in ischemia-reperfusion injury (IRI). Macrophage subtypes, including a novel Lipid-Associated Macrophage (LAM) subtype characterized by high expression of Spp1, Trem2, and other genes, were identified. Enrichment and Progeny pathway analyses highlighted the distinctive functional role of the SPP1+ LAM subtype, particularly in lipidmetabolismand the regulation of the MAPK pathway. Pseudotime analysis revealed the dynamic differentiation of macrophage subtypes during IRI, with the activation of pro- inflammatory pathways in specific clusters. Transcription factor analysis using SCENIC identified key regulators associated with macrophage differentiation. Furthermore, validation in human samples confirmed the presence of SPP1+ LAM. Co-staining experiments provided definitive evidence of LAM marker expression in the infarct zone. These findings shed light on the role of LAM in IRI and its potential as a therapeutic target. Conclusion: In conclusion, the study identifies SPP1+ LAM macrophages in ischemia-reperfusion injury and highlights their potential in cardiac remodeling. [ABSTRACT FROM AUTHOR]

Patients with acute myocardial infarction complicated with diabetes are more likely to develop myocardial ischemia/reperfusion (I/R) injury (MI/RI) during reperfusion therapy. Both HMGB1 and RAGE play important roles in MI/RI. However, the specific mechanisms of HMGB1 associated with RAGE are not fully clarified in diabetic MI/RI. This study aimed to investigate whether the HMGB1-RAGE axis induces diabetic MI/RI via regulating autophagy and apoptosis. A db/db mouse model of MI/RI was established, where anti-HMGB1 antibody and RAGE inhibitor (FPS-ZM1) were respectively injected after 10 min of reperfusion. The results showed that treatment with anti-HMGB1 significantly reduced the infarct size, serum LDH, and CK-MB level. Similar situations also occurred in mice administrated with FPS-ZM1, though the HMGB1 level was unchanged. Then, we found that treatment with anti-HMGB1 or FPS-ZM1 performed the same effects in suppressing the autophagy and apoptosis, as reflected by the results of lower LAMP2 and LC3B levels, increased Bcl-2 level, reduced BAX and caspase-3 levels. Moreover, the Pink1/Parkin levels were also inhibited at the same time. Collectively, this study indicates that the HMGB1-RAGE axis aggravated diabetic MI/RI via apoptosis and Pink1/Parkin mediated autophagy pathways, and inhibition of HMGB1 or RAGE contributes to alleviating those adverse situations. [ABSTRACT FROM AUTHOR]

The death of cardiomyocytes is the basic pathological factor inducing irreversible injury during myocardial ischemia/reperfusion, including increasing infarct size, cardiac remodeling, and heart failure. Despite debates about their precise mechanisms inducing myocardial ischemia/reperfusion (I/R) injury, ferroptosis, necroptosis, and pyroptosis all contribute to the pathological process of myocardial I/R injury. Ferroptosis and necroptosis both occur in the late reperfusion phase and persist for a long time, even though ferroptotic signals appear during ischemia. Pyroptosis, by contrast, takes place in the early reperfusion phase and is tightly related to chronic inflammation via the NLRP3 inflammasome. There is extensive crosstalk between ferroptosis, necroptosis, and pyroptosis, and accumulating evidence indicates an advantage of their combined inhibition to attenuate myocardial I/R injury. Myocardial ischemia–reperfusion (I/R) injury most commonly occurs in coronary artery disease when prompt reperfusion is used to salvage the ischemic myocardium. Cardiomyocyte death is a significant component of myocardial I/R injury and its mechanism was previously thought to be limited to apoptosis and necrosis. With the discovery of novel types of cell death, ferroptosis, necroptosis, and pyroptosis have been shown to be involved in myocardial I/R. These new forms of regulated cell death cause cardiomyocyte loss and exacerbate I/R injury by affecting reactive oxygen species (ROS) generation, calcium stress, and inflammatory cascades, subsequently mediating adverse remodeling, cardiac dysfunction, and heart failure. Herein, we review the roles of ferroptosis, necroptosis, and pyroptosis in myocardial I/R and discuss their contribution to pathology. [ABSTRACT FROM AUTHOR]