Cardiovascular disease (CVD) remains the leading global cause of mortality. Acute myocardial infarction (AMI) refers to acute myocardial ischemia resulting from thrombosis secondary to coronary atherosclerosis, which poses a major threat to human health. Clinically, timely revascularization (reperfusion) represents the basis of clinical treatment for AMI. However, secondary myocardial ischemia-reperfusion injury (MIRI) caused by reperfusion often exacerbates damage, representing a major challenge in clinical practice. Mitochondria represent essential organelles for maintaining cardiac function and cellular bioenergetics in MIRI. In recent years, the role of mitochondrial quality control (MQC) in maintaining cell homeostasis and mediating MIRI has been extensively studied. This review provides a concise overview of MQC mechanisms at the molecular, organelle, and cellular levels and their possible complex regulatory network in MIRI. In addition, potential treatment strategies targeting MQC to mitigate MIRI are summarized, highlighting the gap between current preclinical research and clinical transformation. Overall, this review provides theoretical guidance for further research and clinical translational studies.

Although reperfusion therapy can reduce the mortality of myocardial infarction, it results in myocardial ischemia-reperfusion injury (MIRI). The molecular mechanism by which the interferon-γ pathway affects MIRI is unclear, so we addressed this problem by mining transcriptome and single-cell sequencing data. The GSE160516 and GSE83472 datasets, single cell RNA sequencing (scRNA-seq) data of GSE227088 dataset and 182 interferon-γ pathway related genes (IRGs) were retrieved and incorporated into this study. The differentially expressed genes (DEGs) between MIRI and control samples were searched, the candidate genes were obtained by intersecting DEGs with IRGs. The protein-protein interaction (PPI) analysis was utilized for selecting key genes from candidate genes. Moreover, key genes with significant expression and consistent trend in GSE160516 and GSE83472 datasets were selected as biomarkers. The biological functions and regulatory mechanism of biomarkers were investigated by enrichment analysis and predicting the upstream molecules targeting them. Ulteriorly, cell clusters were identified via unsupervised cluster analysis and merged into different cell types by cell annotation. Cell types in which biomarkers observably and differentially expressed were selected as crucial cell types. Finally, cell communication and pseudo-time analysis were implemented based on crucial cell types. Totally 34 candidate genes were searched by overlapping 1,930 DEGs with 182 IRGs. Nine key genes were singled out from candidate genes, of which Myd88 and Trp53 were significantly upregulated in the MIRI samples of GSE160516 and GSE83472 datasets, so they were identified as biomarkers. Besides, they participated in pathways such as ribosome, spliceosome and cell cycle. Myd88 might be simultaneously regulated by mmu-miR-361-3p and mmu-miR-421-3p, and Trp53 could be regulated by Abl1 and Tead2. Totally 25 cell clusters were merged into six cell types, of which three crucial cell types (cardiomyocyte, fibroblast, and macrophage) could interact with each other through receptor-ligand. Pseudo-time analysis revealed states 1, 2, and 5 of macrophages might be associated with MIRI. Two biomarkers (Myd88 and Trp53) related to IRGs in MIRI were mined, providing a reference for elucidating the mechanism of interferon-γ pathway on MIRI.

Ischemic heart disease (IHD) due to coronary atherosclerosis constitutes the leading cause of morbidity and mortality worldwide. This review was undertaken to retrospectively analyze the lines of research that generated the evidence for our contemporary understanding of atherosclerosis-based coronary artery disease and to provide a rationale for continued support for autopsy-based research in order to make further progress in reduction of the morbidity and mortaility from IHD.

To analyze the contributions of the autopsy to complement and validate other lines of investigation in determining the complex interactions between coronary artery alterations linked to the major manifestations of coronary atherosclerosis, namely, coronary thrombosis, acute myocardial infarction, and sudden cardiac death.

Systematic search on PubMed to gather relevant studies concerning autopsy studies and reviews of the pathology and pathogenesis of atherosclerosis, ischemic heart disease, coronary atherosclerosis, coronary thrombosis, myocardial infarction and sudden cardiac death.

An extensive search of the published literature has confirmed the continuing importance of the autopsy as a powerful tool to understand the pathogenesis, clinical features, and therapeutic options for the treatment of atherosclerosis and its major manifestation, ischemic heart disease. This has been described in the Part I companion of the present review. Autopsy-initiated studies have documented the prevalence and clinicopathological significance of atherosclerosis in different human populations and its relationship to risk factors. It has been shown that the clinically silent phase of ischemic heart disease (IHD) begins in the first decades of life. Pathological studies have clarified the complex relationship between coronary atherosclerosis, coronary thrombosis, and myocardial ischemic events. These studies also have elucidated the pathological basis of sudden cardiac death. Insights from these studies also have been important in developing and evaluating strategies for continued progress in reducing the morbidity and mortality attributed to atherosclerosis and IHD.

This study investigates the preventive benefits of sevoflurane against myocardial ischemia-reperfusion (I/R) injury, focusing on its effect on the modulation of miR-21-5p.

In the clinical study, patients with a history of myocardial ischemia or other conditions requiring surgery were enrolled. Before surgery, the patients were anesthetized with either sevoflurane or propofol. The expression levels of IMA, H-FABP, IL-1β, TNF-α, and IL-6 were also examined. Additionally, the expression of miR-21-5p and its relationships with IMA and H-FABP. A cardiomyocyte hypoxia/reoxygenation (H/R) cell model was created for the in vitro tests. The cells were treated with or without sevoflurane and then transfected with inhibitors of miR-21-5p or a negative control (NC). Evaluations were conducted on cell viability, apoptosis ratio, and oxidative stress indicators (MDA, SOD, and ROS). Furthermore, the expression levels of miR-21-5p, apoptotic markers (BCL-2, BAX), myocardial damage markers (IMA, H-FABP), and inflammatory agents (TNF-α, IL-1β, IL-6) were quantified.

In patients with a history of myocardial ischemia, sevoflurane reduced myocardial I/R injury. These patients also showed upregulation of miR-21-5p, which expression positively linked with levels of IMA. Moreover, in H/R treated cardiac cells, sevoflurane markedly reduced the expression of BAX, MDA, ROS, SOD, inflammatory factor and the apoptotic ratio. Nevertheless, inhibition of miR-21-5p abolished these protective effects. Furthermore, in H/R myocardial cells, sevoflurane increased BCL-2 expression and cell survival; these effects were also countered by blocking miR-21-5p.

Mechanistically, we demonstrate for the first time that sevoflurane alleviates myocardial cell injury in myocardial I/R by upregulating miR-21-5p, thereby reducing inflammation, apoptosis, and oxidative stress in myocardial cells. This finding provides a potential therapeutic target for improving myocardial I/R.

Myocardial ischemia-reperfusion injury (MI/RI) is a critical challenge for acute myocardial infarction therapy, as there is currently no ideal drug available. Glycogen synthase kinase 3 beta (GSK-3β) serves as an promising therapeutic target for treating MI/RI. Our previous studies have demonstrated that Ilex pubescens ameliorates MI/RI. The purpose of this study is to evaluate the therapeutic efficacy and potential mechanism of the screened GSK-3β inhibitor from Ilex pubescens against MI/RI. Three-dimensional-quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, the oxygen and glucose deprivation/reperfusion (OGD/R) and left anterior descending (LAD) artery ligation-induced MI/RI mice model, and western blotting analysis were used to screen and investigate the myocardial protective efficacy and mechanism. Here, we screened Pubescenoside D (PBD) as a GSK-3β inhibitor with an IC50 value of 0.3769 μM from Ilex pubescens, using 3D-QSAR modeling, molecular docking, and kinase assay verification. Ile217, Leu88, Phe93, and Phe67 are the key binding sites for PBD and GSK-3β. PBD protects cardiomyocytes against MI/RI in vitro and in vivo. Further mechanism studies show that PBD inhibits mitochondrial permeability transition pore (mPTP) opening by preventing GSK-3β-mediated the dissociation of hexokinase2 (HK2) from the outer membrane of the mitochondria and enhances mitophagy by suppressing GSK-3β activity, subsequently reducing cardiomyocyte apoptosis. Our findings shed light on the efficacy of PBD as a promising therapeutic agent in the treatment of MI/RI targeting GSK-3β.

Although apelin-13 has cardioprotective impact, its short half-life in the bloodstream has challenged its clinical application. Using nanocarriers can increase the bioavailability, functionality, and stability of drugs. Current investigation aims to find whether apelin13-loaded nano-niosomes confer cardioprotection in an animal model of myocardial ischemia/reperfusion injury (MI/R) via suppressing ferroptosis, targeting Nrf2 pathway, and AMPK/GSK-3β axis. Ligation of the left anterior coronary artery descending was done to establish the MI/R model and 15 μg/kg of apelin13-loaded nano-niosomes were intramyocardially administrated. Echocardiography, RT-PCR, immunohistochemistry, western blot, ELISA kits, and H&E staining were applied to measure the related indicators. Treatment with both apelin13 and apelin13 loaded nano-niosomes could improve cardiac function and attenuate oxidative stress, myocardial inflammatory factors, and hence ferroptosis by activating the Nrf2 and its downstream proteins HO1, NQO1, AMPK/GSK-3β signaling pathway. In conclusion, apelin13-loaded nano-niosomes are effective MI therapeutic agents against MI/R-induced ferroptosis by activation of Nrf2 via AMPK/GSK-3β axis.

Post-cardiac arrest syndrome (PCAS) is characterized by a robust inflammatory response that contributes to significant morbidity and mortality among patients resuscitated from sudden cardiac arrest (SCA). Mitochondrial DNA (mtDNA), with its bacterial-like genomic motifs, has been implicated as a damage-associated molecular pattern in other inflammatory contexts, but its role as a pro-inflammatory stimulus in PCAS has not been studied. Accordingly, the present study was designed to determine if PCAS is characterized by a rise in circulating mtDNA and, if so, whether mtDNA is selectively released, how it activates immune cells, and if targeting mtDNA-sensing pathways attenuates leukocyte activation.

Plasma mtDNA and nuclear DNA (nucDNA) levels were measured in peripheral blood samples collected ∼4-hours post-ROSC from swine with PCAS (n=8) and patients hospitalized after resuscitation from out-of-hospital cardiac arrest (OHCA; n= 57). Additionally, in vitro studies were performed where porcine peripheral blood mononuclear cells (PBMCs) were treated with mtDNA or extracellular vesicles (EVs) isolated from post-ROSC plasma. Pharmacological inhibitors were utilized to inhibit toll-like receptor 9 (TLR9)- and cyclic GMP-AMP synthase (cGAS)-mediated mtDNA sensing.

A significant ∼250-fold elevation in circulating mtDNA was observed shortly after ROSC in swine despite negligible changes in circulating nucDNA, suggesting selective release of mtDNA in PCAS. This finding was corroborated in human OHCA survivors, in which circulating mtDNA was similarly elevated during the early post-ROSC period. Circulating mtDNA was largely encapsulated within EVs in swine and humans, suggesting a conserved mechanism of release across species. In vitro studies demonstrated that PBMC internalization of mtDNA-containing-EVs was required for immune activation and promoted development of a pro-inflammatory leukocyte phenotype characterized by altered surface marker expression and increased release of TNFα, IL-1β, and IL-6. Disrupting EVs or degrading enclosed DNA attenuated these responses, which were partially restored upon reintroduction of mtDNA. Pharmacological blockade of TLR9 or cGAS pathways significantly reduced mtDNA-induced inflammation, providing insight regarding signaling pathways that may be targeted to modulate mtDNA-mediated immune activation in PCAS.

These novel findings demonstrate that brief whole-body ischemia and reperfusion in the context of resuscitation from SCA triggers selective mtDNA release, primarily within EVs, that acts as a potent driver of immune activation in PCAS. By linking EV-encapsulated mtDNA to TLR9 and cGAS activation, this study provides a foundation for the development of novel therapeutic interventions aimed at limiting mtDNA release or disrupting its downstream sensing pathways to enhance survival and improve outcomes after SCA.

What is new?: Our study reveals that circulating mitochondrial DNA (mtDNA), primarily encapsulated in extracellular vesicles (EV), is selectively released into the bloodstream after resuscitation from sudden cardiac arrest.EV-encapsulated mtDNA triggers immune cell activation, evidenced by phenotypic shifts toward inflammatory dendritic cells and macrophages, as well as increased pro-inflammatory cytokine secretion.Pharmacological inhibition of TLR9 and cGAS pathways significantly attenuates the mtDNA-induced inflammatory response, pointing to novel therapeutic avenues for modulating post-resuscitation immune activation in patients with post-cardiac arrest syndrome (PCAS).What are the clinical implications?: Identification of mtDNA as a key driver of sterile inflammation in PCAS highlights a potential target for interventions aimed at reducing multi-organ damage and improving neurological outcomes.Therapeutic strategies to block mtDNA release or downstream signaling (e.g., TLR9/cGAS inhibition) may limit harmful pro-inflammatory cascades and bolster long-term survival following resuscitation from cardiac arrest.Early clinical screening for elevated EV-encapsulated mtDNA could help refine prognostic evaluations, complement current biomarkers, and guide personalized therapy to lessen the inflammatory burden of PCAS.

Myocardial infarction (MI) is a severe hypoxic event, resulting in the loss of up to one billion cardiomyocytes (CMs). Due to the limited intrinsic regenerative capacity of the heart, cell-based regenerative therapies, which feature the implantation of stem cell-derived cardiomyocytes (SC-CMs) into the infarcted myocardium, are being developed with the goal of restoring lost muscle mass, re-engineering cardiac contractility, and preventing the progression of MI into heart failure (HF). However, such cell-based therapies are challenged by their susceptibility to oxidative stress in the ischemic environment of the infarcted heart. To maximize the therapeutic benefits of cell-based approaches, a better understanding of the heart environment at the cellular, tissue, and organ level throughout MI is imperative. This review provides a comprehensive summary of the cardiac pathophysiology occurring during and after MI, as well as how these changes define the cardiac environment to which cell-based cardiac regenerative therapies are delivered. This understanding is then leveraged to frame how cell culture treatments may be employed to enhance SC-CMs' hypoxia resistance. In this way, we synthesize both the complex experience of SC-CMs upon implantation and the engineering techniques that can be utilized to develop robust SC-CMs for the clinical translation of cell-based cardiac therapies.

Ca2+ overload and mitochondrial dysfunction play crucial roles in myocardial ischemia-reperfusion (I/R) injury. Piezo1, a mechanosensitive cation channel, is essential for intracellular Ca2+ homeostasis. The objective of this research was to explore the effects of Piezo1 on mitochondrial function during myocardial I/R injury. We showed that the expression of myocardial Piezo1 was elevated in the infracted area of I/R and cardiomyocyte-specific Piezo1 deficiency (Piezo1△Myh6) mice attenuated I/R by decreasing infarct size and cardiac dysfunction. Piezo1△Myh6 regulated mitochondrial fusion and fission to improve mitochondrial function and decrease inflammation and oxidative stress in vivo and in vitro. Mechanistically, myocardial Piezo1 knockout alleviated intracellular calcium overload to normalize calpain-associated mitochondrial homeostasis. Our findings indicated that Piezo1 depletion in cardiomyocytes partially restored mitochondrial homeostasis during cardiac ischemia/reperfusion (I/R) injury. This study suggests an innovative therapeutic strategy to alleviate cardiac I/R injury.

Reperfusion of the ischaemic heart is essential to limit myocardial infarction. However, reperfusion can cause cardiomyocyte hypercontracture. Recently, cardiac myosin-targeted inhibitors (CMIs), such as Mavacamten (MYK-461) and Aficamten (CK-274), have been developed to treat patients with cardiac hypercontractility. These CMIs are well tolerated and safe in clinical trials. We hypothesised that, by limiting hypercontraction, CMIs may reduce hypercontracture and protect hearts in the setting of ischaemia and reperfusion (IR).

We investigated the ability of MYK-461 and CK-274 to inhibit hypercontracture of adult rat cardiomyocytes (ARVC) in vitro following ATP depletion. A suitable dose of CMIs for subsequent in vivo IR studies was identified using cardiac echocardiography of healthy male Sprague Dawley rats. Rats were anaesthetized and subject to coronary artery ligation for 30 min followed by 2 h of reperfusion. Prior to reperfusion, CMI or vehicle was administered intraperitoneally. Ischaemic preconditioning (IPC) was used as a positive control group. Infarct size was assessed by tetrazolium chloride staining and extent of hypercontracture was assessed by histological staining.

Treatment with CMIs inhibited ARVC hypercontracture in vitro. MYK-461 (2 mg/kg) and CK-274 (0.5 mg/kg to 2 mg/kg) significantly reduced infarct size vs. vehicle. IR caused extensive contraction band necrosis, which was reduced significantly by IPC but not by CMIs, likely due to assay limitations. GDC-0326, an inhibitor of PI3Kα, abrogated CK-274-mediated protection following IR injury. GDC-0326 reduced phosphorylation of AKT when administered together with CK-274.

This study identifies CMIs as novel cardioprotective agents in the setting of IR injury.

Myocardial infarction (MI) is a life-threatening condition that leads to loss of viable heart tissue. The best way to treat acute MI and limit the infarct size is to re-open the occluded coronary artery and restore the supply of oxygenated and nutrient-rich blood, but reperfusion can cause additional damage. Autophagy is an intracellular process that recycles damaged cytoplasmic components (molecules and organelles) by loading them into autophagosomes and degrading them in autolysosomes. Autophagy is increased in in vivo animal models of permanent ischemia and ischemia/reperfusion but by different molecular mechanisms. While autophagy is protective during permanent ischemia, it is detrimental during ischemia/reperfusion. Its modulation is being investigated as a potential target to reduce reperfusion injury. This review provides a synopsis of the current knowledge about autophagy, summarizes findings specifically in permanent ischemia and ischemia/reperfusion, and briefly discusses the potential implication of experimental findings.

H2S is an endogenous gas signal molecule, which protects cerebral ischemia/reperfusion (I/R) injury by phosphorylating rho-associated coiled coil-containing protein kinase 2 (ROCK2) at Tyr722, and inhibiting ROCK2 protein expression and activities. We previously reported that H2S protected rat neurons from hypoxia/reoxygenation injury in vitro through inhibiting phosphorylation of ROCK2 at Thr436 and Ser575, but it is unclear whether these two sites are involved in protection of H2S against cerebral I/R injury.

Rats transfected with wild-type and mutant eukaryotic plasmids of ROCK2 in hippocampus were used to establish I/R model by ligating bilateral common carotid artery. Rat behavioral deficit was detected by water maze assay, and ROCK2, lactate dehydrogenase (LDH), nerve-specific enolase (NSE) and reactive oxygen species (ROS) were determined by ELISA. ROCK2 expressions was examined by western-blot assay, and bcl-2 and Bax mRNAs were examined by RT-qPCR.

NaHS (4.8 mg/kg) significantly inhibited the I/R-increased serum LDH, NSE and ROS in the ROCK2wild-pEGFP-N1-transfected rats, but had no obvious effect in the ROCK2T436A-pEGFP-N1- or the ROCK2S575F-pEGFP-N1-transfected rats; inhibitions of NaHS on the I/R-increased escape latency and the I/R-decreased percentage of target quadrant distance to total distance were markedly attenuated or abolished in the ROCK2T436A-pEGFP-N1- or the ROCK2S575F-pEGFP-N1-transfected rats compared with those in the ROCK2wild-pEGFP-N1-transfected rats; NaHS obviously inhibited the I/R-increased hippocampal ROCK2 and GFP-ROCK2 proteins, Bax mRNA, and ROCK2 activity, as well as the I/R-decreased hippocampal bcl-2 mRNA in the hippocampus of the ROCK2wild-pEGFP-N1-transfected rats, but had no significant effect in the ROCK2T436A-pEGFP-N1- or the ROCK2S575F-pEGFP-N1-transfected rats.

H2S protects cerebral I/R injury in rats by inhibiting expression and activation of hippocampal ROCK2 via the Thr436 and Ser575 sites.

Tanshinone, a natural compound found in the roots of Salvia miltiorrhiza, has been shown to possess various pharmacological properties, including anti-inflammatory, antioxidant, and cardiovascular protective effects. This article aims to review the literature on the cardiovascular protective effects of tanshinone and its underlying mechanisms. Tanshinone has been demonstrated to improve cardiac function, reduce oxidative stress, and inhibit inflammation in various animal models of cardiovascular diseases. Additionally, it has been shown to regulate multiple signaling pathways involved in the pathogenesis of cardiovascular diseases, such as the PI3K/AKT, MAPK, and NF-κB pathways. Clinical studies have also suggested that tanshinone may have therapeutic potential for treating cardiovascular diseases. In conclusion, tanshinone has emerged as a promising natural compound with significant cardiovascular protective effects, and further research is warranted to explore its potential clinical applications.

This review presents a perspective on the pathobiology of acute myocardial infarction, a major manifestation of ischemic heart disease, and related mechanisms of ischemic and toxic cardiomyocyte injury, based on advances and insights that have accrued over the last seventy years, including my sixty years of involvement in the field as a physician-scientist-pathologist. This analysis is based on integration of my research within the broader context of research in the field. A particular focus has been on direct measurements in cardiomyocytes of electrolyte content by electron probe X-ray microanalysis (EPXMA) and Ca2+ fluxes by fura-2 microspectrofluorometry. These studies established that increased intracellular Ca2+ develops at a transitional stage in the progression of cardiomyocyte injury in association with ATP depletion, other electrolyte alterations, altered cell volume regulation, and altered membrane phospholipid composition. Subsequent increase in total calcium with mitochondrial calcium accumulation can occur. These alterations are characteristic of oncosis, which is an initial pre-lethal state of cell injury with cell swelling due to cell membrane dysfunction in ATP depleted cells; oncosis rapidly progresses to necrosis/necroptosis with physical disruption of the cell membrane, unless the adverse stimulus is rapidly reversed. The observed sequential changes fit a three-stage model of membrane injury leading to irreversible cell injury. The data establish oncosis as the primary mode of cardiomyocyte injury in evolving myocardial infarcts. Oncosis also has been documented to be the typical form of non-ischemic cell injury due to toxins. Cardiomyocytes with less energy impairment have the capability of undergoing apoptosis and autophagic death as well as oncosis, as is seen in pathological remodeling in chronic heart failure. Work is ongoing to apply the insights from experimental studies to better understand and ameliorate myocardial ischemia and reperfusion injury in patients. The perspective and insights in this review are derived from basic principles of pathology, an integrative discipline focused on mechanisms of disease affecting the cell, the organizing unit of living organisms.

Macrophage-mediated inflammation plays a crucial role in the pathophysiological process of myocardial ischemia/reperfusion (I/R) injury. Recent studies have highlighted the importance of mitochondrial function and inflammasome activation in the inflammatory process. Kirenol, a well-known natural compound, has been shown to regulate inflammation in various diseases. This study investigated whether Kirenol could exert anti-inflammatory effects on macrophages during myocardial I/R injury.

Mouse myocardial I/R models were established by 45 min of ischemia followed by 24 h of reperfusion. Saline or Kirenol treatment was administered. In vivo assessments included the evaluation of cardiac function, infarcted area, and immune cell infiltration. Subsequently, bone marrow-derived macrophages (BMDMs) were isolated, and mitochondrial function and pyroptosis were assessed. Furthermore, the study compared the cardioprotective effects of Kirenol with a specific NOX1/NOX4 inhibitor, GKT137831.

Kirenol gavage improved cardiac function, decreased infarct area, and alleviated inflammatory infiltration in mice subjected to myocardial I/R injury. Mechanistically, Kirenol inhibited NOX1 and NOX4 and enhanced mitochondrial function, ultimately attenuating the pyroptosis of macrophages. The therapeutic effects of Kirenol and GKT137831 were not significantly different.

This study demonstrates that Kirenol mitigates myocardial I/R injury by inhibiting NOX1 and NOX4, restoring mitochondrial function, and ameliorating macrophage pyroptosis.

Background/Objectives: Hemodialysis-induced myocardial stunning (HIMS) is a frequent complication in patients undergoing maintenance hemodialysis, characterized by transient left ventricular dysfunction due to ischemic episodes. Mitochondrial dysfunction and fluctuations in key ions such as potassium (K+) and calcium (Ca2+) are implicated in the pathogenesis of HIMS. This study aims to investigate the role of mitochondrial dysfunction and the protective potential of mitochondrial ATP-sensitive potassium channels (mitoKATP) in mitigating HIMS. Methods: A 5/6 nephrectomy rat model was established to mimic chronic kidney disease and the subsequent HIMS. The effects of mitoKATP channel modulators were evaluated by administering diazoxide (DZX), a mitoKATP opener, and 5-hydroxydecanoate (5-HD), a mitoKATP blocker, before hemodialysis. Mitochondrial function was assessed by measuring membrane potential, ATP synthase activity, and intramitochondrial Ca2+ levels. Myocardial function was evaluated using speckle tracking echocardiography. Results: Rats undergoing hemodialysis exhibited significant reductions in left ventricular strain and synchrony. DZX administration significantly improved mitochondrial function and reduced myocardial strain compared to controls. Conversely, 5-HD worsened mitochondrial swelling and disrupted myocardial function. Higher K+ and Ca2+ concentrations in the dialysate were associated with improved mitochondrial energy metabolism and myocardial strain. Conclusions: Mitochondrial dysfunction and ion imbalances during hemodialysis are key contributors to HIMS. The activation of mitoKATP channels provides mitochondrial protection and may serve as a potential therapeutic strategy to mitigate HIMS.

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.

Understanding of the mechanisms contributing to the increased maternal susceptibility for major adverse cardiovascular events in the postpartum period remains poor. Accordingly, this study tested the hypothesis that the balance between coronary blood flow and myocardial metabolism is compromised during the puerperium period (35-45 days post-delivery) in swine. Systemic and coronary hemodynamic responses were assessed in anesthetized, open-chest control (nonpregnant) and puerperium/postpartum swine at baseline and in response to intravenous infusion of dobutamine (1-30 μg/kg/min). Blood pressure and heart rate were lower in postpartum swine at baseline and in response to dobutamine (P < 0.05). Coronary blood flow and myocardial oxygen delivery were significantly diminished at baseline in postpartum swine (P < 0.001), which corresponded with ∼35% reduction in myocardial oxygen consumption (MVO2) (P < 0.001). Postpartum swine displayed enhanced retrograde coronary flow, larger cardiomyocyte area (P < 0.01) and marked capillary rarefaction (P < 0.01). The relationship between coronary blood flow and heart rate (P < 0.05) or MVO2 (P < 0.001) was significantly diminished in postpartum swine as dobutamine increased MVO2 up to ∼135% in both groups. This reduction in myocardial perfusion was associated with decreases in myocardial lactate uptake (P < 0.001), increases in coronary venous PCO2 (P < 0.01) and decreased coronary venous pH (P < 0.01). These findings suggest an impaired balance between coronary blood flow and myocardial metabolism could contribute to the increased incidence of maternal myocardial ischemia and premature death in the postpartum period.

Accumulating evidence suggests that electroacupuncture (EA) has obvious therapeutic effects and unique advantages in alleviating myocardial ischemia-reperfusion injury (MIRI), while the underlying neuromolecular mechanisms of EA intervention for MIRI have not been fully elucidated. The aim of the study is to investigate the role of the neural pathway of hypothalamic paraventricular nucleus (PVN) neurons projecting to the rostral ventrolateral medulla (RVLM) in the alleviation of MIRI rats by EA preconditioning. MIRI models were established by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for 2 h. Electrocardiogram recording, chemogenetics, enzyme-linked immunosorbent assay, multichannel physiology recording and haematoxylin-eosin and immunofluorescence staining methods were conducted to demonstrate that the firing frequencies of neurons in the PVN and the expression of c-Fos decreased by EA pretreatment. Meanwhile, EA preconditioning significantly reduced the levels of creatine kinase isoenzymes (CK-MB), cardiac troponin I (cTnI) and lactic dehydrogenase (LDH). Virus tracing showed a projection connection between PVN and RVLM. The inhibition of the PVN-RVLM neural pathway could replicate the protective effect of EA pretreatment on MIRI rats. However, the activation of the pathway weakened the effect of EA preconditioning. EA pretreatment alleviated MIRI by regulating PVN neurons projecting to RVLM. This work provides novel evidence of EA pretreatment for alleviating MIRI.

Myocardial ischemia-reperfusion injury (MIRI) is defined as the restoration of blood flow to the myocardium after a brief interruption of blood supply, causing more severe damage to the ischemic myocardium. However, currently, reperfusion therapy is the preferred therapy for ischemic cardiomyopathy, which undoubtedly causes MIRI, and thus it has become a challenging issue affecting the prognosis of coronary artery disease.

A search was conducted in the Web of Science Core Collection database for papers relevant to MIRI therapy published between 1 January 2000 and 1 October 2023. Bibliometric analyses were performed using VOSviewer and CiteSpace to elucidate the progress and hotspots.

3304 papers from 64 countries, 2134 research institutions and 13,228 authors were enrolled in the study. Of these, China contributed the most papers and had the biggest impact, while the United States had the most extensive partnership. The Fourth Military Medical University was the primary research institution. The most valuable authors include Chattipakorn, Nipon, Chattipakorn, Siriporn c, Yang, Jian and Yang, Yang.

Over the past 20 years, research on MIRI therapies has made significant strides. Further studies are necessary to explore the interactions between various therapeutic options. Future investigations will emphasize nanocarriers, cardiac regeneration, and stem cell therapies. Our study identifies MIRI research hotspots from a bibliometric perspective, forecasts future trends, and offers fresh insights into MIRI therapy research.

Acute myocardial infarction (AMI) is one of the most prevalent cardiovascular diseases, accounting for a high incidence rate and high mortality worldwide. Hypoxia/reoxygenation (H/R)-induced myocardial cell injury is the main cause of AMI. Several studies have shown that circular RNA contributes significantly to the pathogenesis of AMI. Here, we established an AMI mouse model to investigate the effect of circDiaph3 in cardiac function and explore the functional role of circDiaph3 in H/R-induced cardiomyocyte injury and its molecular mechanism. Bioinformatics tool and RT-qPCR techniques were applied to detect circDiaph3 expression in human patient samples, heart tissues of AMI mice, and H/R-induced H9C2 cells. CCK-8 was used to examine cell viability, while annexin-V/PI staining was used to assess cell apoptosis. Myocardial reactive oxygen species (ROS) levels were detected by immunofluorescence. Western blot was used to detect the protein expression of anti-apoptotic Bcl-2 while pro-apoptotic Bax and cleaved-Caspase-3. Furthermore, ELISA was used to detect inflammatory cytokines production. While bioinformatics tool and RNA pull-down assay were used to verify the interaction between circDiaph3 and miR-338-3p. We found that circDiaph3 expression was high in AMI patients and mice, as well as in H/R-treated H9C2 cells. CircDiaph3 silencing ameliorated apoptosis and inflammatory response of cardiomyocytes in vivo. Moreover, the knockdown of cirDiaph3 mitigated H/R-induced apoptosis and the release of inflammatory mediators like IL-1β, IL-6, and TNF-α in H9C2 cells. Mechanistically, circDiaph3 induced cell apoptosis and inflammatory responses in H/R-treated H9C2 cells by sponging miR-338-3p. Overexpressing miR-338-3p in H/R-treated cells prominently reversed circDiaph3-induced effects. Notably, miR-338-3p inhibited SRSF1 expression in H/R-treated H9C2 cells. While overexpressing SRSF1 abrogated miR-338-3p-mediated alleviation of apoptosis and inflammation after H/R treatment. To summarize, circDiaph3 aggravates H/R-induced cardiomyocyte apoptosis and inflammation through the miR-338-3p/SRSF1 axis. These findings suggest that the circDiaph3/miR-338-3pp/SRSF1 axis could be a potential therapeutic target for treating H/R-induced myocardial injury.

Efferocytosis, mediated by the macrophage receptor MerTK (myeloid-epithelial-reproductive tyrosine kinase), is a significant contributor to cardiac repair after myocardial ischemia-reperfusion (MI/R) injury. However, the death of resident cardiac macrophages (main effector cells), inactivation of MerTK （main effector receptor), and overexpression of "do not eat me" signals (brake signals, such as CD47), collectively lead to the impediment of efferocytosis in the post-MI/R heart. To date, therapeutic strategies targeting individual above obstacles are relatively lacking, let alone their effectiveness being limited due to constraints from the other concurrent two. Herein, inspired by the application research of chimeric antigen receptor macrophages (CAR-Ms) in solid tumors, a genetically modified macrophage-based synergistic drug delivery strategy that effectively challenging the three major barriers in an integrated manner is developed. This strategy involves the overexpression of exogenous macrophages with CCR2 (C-C chemokine receptor type 2) and cleavage-resistant MerTK, as well as surface clicking with liposomal PEP-20 (a CD47 antagonist). In MI/R mice model, this synergistic strategy can effectively restore cardiac efferocytosis after intravenous injection, thereby alleviating the inflammatory response, ultimately preserving cardiac function. This therapy focuses on inhibiting the initiation and promoting active resolution of inflammation, providing new insights for immune-regulatory therapy.

The present study aimed to explore how resveratrol (Res) confers myocardial protection by attenuating ferroptosis. In vivo and in vitro myocardial ischemia/reperfusion injury (MIRI) models were established, with or without Res pretreatment. The results showed that Res pretreatment effectively attenuated MIRI, as evidenced by increased cell viability, reduced lactate dehydrogenase activity, decreased infarct size, and maintained cardiac function. Moreover, Res pretreatment inhibited MIRI-induced ferroptosis, as shown by improved mitochondrial integrity, increased glutathione level, decreased prostaglandin-endoperoxide synthase 2 level, inhibited iron overload, and abnormal lipid peroxidation. Of note, Res pretreatment decreased or increased voltage-dependent anion channel 1/glutathione peroxidase 4 (VDAC1/GPX4) expression, which was increased or decreased via anoxia/reoxygenation (A/R) treatment, respectively. However, the overexpression of VDAC1 via pAd/VDAC1 and knockdown of GPX4 through Si-GPX4 reversed the protective effect of Res in A/R-induced H9c2 cells, whereas the inhibition of GPX4 with RSL3 abolished the protective effect of Res on mice treated with ischemia/reperfusion.Interestingly, knockdown of VDAC1 by Si-VDAC1 promoted the protective effect of Res on A/R-induced H9c2 cells and the regulation of GPX4. Finally, the direct interaction between VDAC1 and GPX4 was determined using co-immunoprecipitation. In conclusion, Res pretreatment could protect the myocardium against MIRI-induced ferroptosis via the VDAC1/GPX4 signaling pathway.

Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.

Myocardial ischemia/reperfusion (I/R) injury is a clinical challenge in the treatment of ischemic heart disease. The present study aimed to establish a hypoxia/reoxygenation (H/R)-induced H9c2 cell model to explore the role and mechanism of chemokine-like factor 1 (CKLF1) in myocardial I/R injury. First, CKLF1 expression was measured in H/R-induced H9c2 cells by reverse transcription-quantitative PCR and western blotting. Subsequently, after CKLF1 silencing, cell viability and apoptosis were evaluated by Cell Counting Kit-8 assay and flow cytometry. In addition, 2,7-dichlorodihydrofluorescein diacetate staining was used to assess the levels of cellular reactive oxygen species. Additionally, the levels of superoxide dismutase, glutathione peroxidase and malondialdehyde, and the contents of inflammatory factors IL-6, IL-1β and TNF-α were detected using corresponding commercially available kits. Western blotting was used to examine the expression levels of proteins involved in the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. The JASPAR database predicted that forkhead box protein C1 (FOXC1) would bind to the CKLF1 promoter region, and dual luciferase and chromatin immunoprecipitation assays were performed to verify it. Subsequently, FOXC1 overexpression and CKLF1 silencing were used to clarify the regulatory mechanism of FOXC1 on CKLF1 in H/R-induced H9c2 cells. The results revealed that CKLF1 expression was markedly enhanced in H/R-stimulated H9c2 cells. CKLF1 knockdown enhanced the viability and inhibited the apoptosis of H9c2 cells exposed to H/R. Moreover, the oxidative stress and inflammation induced by H/R were alleviated following CKLF1 silencing. CKLF1 knockdown also inhibited NLRP3 inflammasome activation. Furthermore, FOXC1 bound to the CKLF1 promoter region to upregulate CKLF1 expression, and FOXC1 overexpression alleviated the effects of CKLF1 knockdown on H9c2 cell damage induced by H/R via activation of the NLRP3 inflammasome. In conclusion, CKLF1 transcriptionally activated by FOXC1 may promote H/R-induced oxidative stress and inflammation in H9c2 cells via NLRP3 inflammasome activation.

Acute kidney injury is a severe disease that is closely associated with substantial morbidity and mortality. The most common cause of AKI is renal ischemia-reperfusion injury. Mesenchymal stem cells (MSCs) have previously been shown to have renoprotective effects. However, extracellular vesicles secreted by MSCs are thought to be the key for the therapeutic effects of MSCs. This study investigated whether small EVs derived from ACE2-modified human umbilical cord MSCs could alleviate RIRI and explored their underlying molecular mechanisms METHODS: A lentivirus carrying an ACE2 overexpression vector was constructed and used to infect MSCs. The small EVs were isolated from MSC-conditioned medium by ultracentrifugation. HK-2 cells were cocultured with MSC-ACE2-EVs and subjected to hypoxia/reoxygenation injury. MSCs-ACE2-EVs were injected into RIRI mice. Biochemical and morphological characteristics were assessed, and the levels of inflammatory-related factors, oxidative stress products, and apoptosis in HK-2 cells and kidney tissues were assessed RESULTS: In vitro, MSC-ACE2-EVs had stronger anti-inflammatory, antioxidative stress, and antiapoptotic effects in HK-2 cells subjected to H/R than MSC-NC-EVs. In vivo, MSC-ACE2-EVs could target the injured kidney, reduce blood creatinine and urea nitrogen levels, and protect the kidney from I/R, and this effect may have been related to the activation of the Nrf2/HO-1 signalling pathway CONCLUSION: Taken together, our results demonstrated the anti-inflammatory, antioxidative stress, and antiapoptotic effects of MSC-ACE2-EVs, which protected against I/R injury in vitro and vivo. MSC-ACE2-EVs may be therapeutic agents for RIRI.

Cardiopulmonary resuscitation and related life support technologies have improved substantially in recent years; however, mortality and disability rates from cardiac arrest (CA) remain high and are closely associated with the high incidence of cerebral ischemia-reperfusion injury (CIRI), which is explained by a "double-hit" model (i.e., resulting from both ischemia and reperfusion). Mitochondria are important power plants in the cell and participate in various biochemical processes, such as cell differentiation and signaling in eukaryotes. Various mitochondrial processes, including energy metabolism, calcium homeostasis, free radical production, and apoptosis, are involved in several important stages of the progression and development of CIRI. Mitophagy is a key mechanism of the endogenous removal of damaged mitochondria to maintain organelle function and is a critical target for CIRI treatment after CA. Mitophagy also plays an essential role in attenuating ischemia-reperfusion in other organs, particularly during post-cardiac arrest myocardial dysfunction. Regulation of mitophagy may influence necroptosis (a programmed cell death pathway), which is the main endpoint of organ ischemia-reperfusion injury. In this review, we summarize the main signaling pathways related to mitophagy and their associated regulatory proteins. New therapeutic methods and drugs targeting mitophagy in ischemia-reperfusion animal models are also discussed. In-depth studies of the mechanisms underlying the regulation of mitophagy will enhance our understanding of the damage and repair processes in CIRI after CA, thereby contributing to the development of new therapeutic strategies.

Inhibition of the mammalian target of rapamycin (mTOR) with the macrolide rapamycin or pharmacological suppression of KATP channel opening translated to scar expansion of the myocardial infarcted (MI) adult female rodent heart. The present study tested the hypotheses that rapamycin-mediated scar expansion was sex-specific and that mTOR signaling directly influenced KATP channel subunit expression/activity. Scar size was significantly larger in post-MI male rats as compared to the previous data reported in post-MI female rats. The reported scar expansion of rapamycin-treated post-MI female rats was not observed following the administration of the macrolide to post-MI male rats. Protein levels of the KATP channel subunits Kir6.2 and SUR2A and phosphorylation of the serine2448 residue of mTOR were similar in the normal heart of adult male and female rats. By contrast, greater tuberin inactivation characterized by the increased phosphorylation of the threonine1462 residue and reduced raptor protein levels were identified in the normal heart of adult female rats. Rapamycin pretreatment of phorbol 12,13-dibutyrate (PDBu)-treated neonatal rat ventricular cardiomyocytes (NNVMs) suppressed hypertrophy, inhibited p70S6K phosphorylation, and attenuated SUR2A protein upregulation. In the presence of low ATP levels, KATP channel activity detected in untreated NNVMs was significantly attenuated in PDBu-induced hypertrophied NNVMs via a rapamycin-independent pathway. Thus, rapamycin administration to post-MI rats unmasked a sex-specific pattern of scar expansion and mTOR signaling in PDBu-induced hypertrophied NNVMs significantly increased SUR2A protein levels. However, the biological advantage associated with SUR2A protein upregulation was partially offset by an mTOR-independent pathway that attenuated KATP channel activity in PDBu-induced hypertrophied NNVMs.

(1) Background: Despite the evidence that ferroptosis is involved in myocardial ischemia-reperfusion (MIR), the critical regulator of ferroptosis in MIR remains unclear. (2) Methods: We included three GEO datasets and a set of ferroptosis-related genes with 259 genes. Following the identification of the differentially expressed ferroptosis-related genes (DEFRGs) and hub genes, we performed the functional annotation, protein-protein interaction network, and immune infiltration analysis. The GSE168610 dataset, a cell model, and an animal model were then used to verify key genes. (3) Results: We identified 17 DEFRGs and 9 hub genes in the MIR samples compared to the control. Heme oxygenase 1 (Hmox1), activating transcription factor 3 (Atf3), epidermal growth factor receptor (Egfr), and X-box binding protein 1 (Xbp1) were significantly upregulated in response to ischemic and hypoxic stimuli. In contrast, glutathione peroxidase 4 (Gpx4) and vascular endothelial growth factor A (Vegfa) were consistently decreased in either the oxygen and glucose deprivation/reoxygenation cell or the MIR mouse model. (4) Conclusions: This study emphasized the relevance of ferroptosis in MIR. It has been successfully demonstrated that nine ferroptosis-related genes (Hmox1, Atf3, Egfr, Gpx4, Cd44, Vegfa, asparagine synthetase (Asns), Xbp1, and bromodomain containing 4 (Brd4)) are involved in the process. Additional studies are needed to explore potential therapeutic targets for MIR.

Cardiovascular diseases are one of the leading causes of mortality in developed countries. Among cardiovascular disorders, myocardial infarction remains a life-threatening problem predisposing to the development and progression of ischemic heart failure. Ischemia/reperfusion (I/R) injury is a critical cause of myocardial injury. In recent decades, many efforts have been made to find the molecular and cellular mechanisms underlying the development of myocardial I/R injury and post-ischemic remodeling. Some of these mechanisms are mitochondrial dysfunction, metabolic alterations, inflammation, high production of ROS, and autophagy deregulation. Despite continuous efforts, myocardial I/R injury remains a major challenge in medical treatments of thrombolytic therapy, heart disease, primary percutaneous coronary intervention, and coronary arterial bypass grafting. The development of effective therapeutic strategies to reduce or prevent myocardial I/R injury is of great clinical significance.

Reperfusion injury is a very common complication of various indicated therapies such as the re-opening of vessels in the myocardium or brain as well as reflow in hemodynamic shutdown (cardiac arrest, severe trauma, aortic cross-clamping). The treatment and prevention of reperfusion injury has therefore been a topic of immense interest in terms of mechanistic understanding, the exploration of interventions in animal models and in the clinical setting in major prospective studies. While a wealth of encouraging results has been obtained in the lab, the translation into clinical success has met with mixed outcomes at best. Considering the still very high medical need, progress continues to be urgently needed. Multi-target approaches rationally linking interference with pathophysiological pathways as well as a renewed focus on aspects of microvascular dysfunction, especially on the role of microvascular leakage, are likely to provide new insights.

The problems associated with economic development and social progress have led to an increase in the occurrence of cardiovascular diseases (CVDs), which affect the health of an increasing number of people and are a leading cause of disease and population mortality worldwide. Endoplasmic reticulum stress (ERS), a hot topic of interest for scholars in recent years, has been confirmed in numerous studies to be an important pathogenetic basis for many metabolic diseases and play an important role in maintaining physiological processes. The endoplasmic reticulum (ER) is a major organelle that is involved in protein folding and modification synthesis, and ERS occurs when several physiological and pathological factors allow excessive amounts of unfolded/misfolded proteins to accumulate. ERS often leads to initiation of the unfolded protein response (UPR) in a bid to re-establish tissue homeostasis; however, UPR has been documented to induce vascular remodeling and cardiomyocyte damage under various pathological conditions, leading to or accelerating the development of CVDs such as hypertension, atherosclerosis, and heart failure. In this review, we summarize the latest knowledge gained concerning ERS in terms of cardiovascular system pathophysiology, and discuss the feasibility of targeting ERS as a novel therapeutic target for the treatment of CVDs. Investigation of ERS has immense potential as a new direction for future research involving lifestyle intervention, the use of existing drugs, and the development of novel drugs that target and inhibit ERS.

Mitochondrial inner membrane protein (Mitofilin/Mic60) is part of a big complex that constituent the mitochondrial inner membrane organizing system (MINOS), which plays a critical role in maintaining mitochondrial architecture and function. We recently showed that Mitofilin physically binds to Cyclophilin D, and disruption of this interaction promotes the opening of mitochondrial permeability transition pore (mPTP) and determines the extent of I/R injury. Here, we investigated whether Mitofilin knockout in the mouse enhances myocardial injury and inflammation after I/R injury. We found that full-body deletion (homozygote) of Mitofilin induces a lethal effect in the offspring and that a single allele expression of Mitofilin is sufficient to rescue the mouse phenotype in normal conditions. Using non-ischemic hearts from wild-type (WT) and Mitofilin+/- (HET) mice, we report that the mitochondria structure and calcium retention capacity (CRC) required to induce the opening of mPTP were similar in both groups. However, the levels of mitochondrial dynamics proteins involved in both fusion/fission, including MFN2, DRP1, and OPA1, were slightly reduced in Mitofilin+/- mice compared to WT. After I/R, the CRC and cardiac functional recovery were reduced while the mitochondria structure was more damaged, and myocardial infarct size was increased in Mitofilin+/- mice compared to WT. Mitofilin+/- mice exhibited an increase in the mtDNA release in the cytosol and ROS production, as well as dysregulated SLC25As (3, 5, 11, and 22) solute carrier function, compared to WT. In addition, Mitofilin+/- mice displayed an increase in the transcript of pro-inflammatory markers, including IL-6, ICAM, and TNF-α. These results suggest that Mitofilin knockdown induces mitochondrial cristae damage that promotes dysregulation of SLC25As solute carriers, leading to an increase in ROS production and reduction in CRC after I/R. These effects are associated with an increase in the mtDNA release into the cytosol, where it activates signaling cascades leading to nuclear transcription of pro-inflammatory cytokines that aggravate I/R injury.

Our untargeted metabolic data unveiled that Acyl-CoAs undergo dephosphorylation, however little is known about these novel metabolites and their physiology/pathology relevance.

To understand the relationship between acyl-CoAs dephosphorylation and energy status as implied in our previous work, we seek to investigate how ischemia (energy depletion) triggers metabolic changes, specifically acyl-CoAs dephosphorylation in this work.

Rat hearts were isolated and perfused in Langendorff mode for 15 min followed by 0, 5, 15, and 30 minutes of global ischemia. The heart tissues were harvested for metabolic analysis.

As expected, ATP and phosphocreatine were significantly decreased during ischemia. Most short- and medium-chain acyl-CoAs progressively increased with ischemic time from 0 to 15 min, whereas a 30-minute ischemia did not lead to further change. Unlike other acyl-CoAs, propionyl-CoA accumulated progressively in the hearts that underwent ischemia from 0 to 30 min. Progressive dephosphorylation occurred to all assayed acyl-CoAs and free CoA regardless their level changes during the ischemia.

The present work further confirms that dephosphorylation of acyl-CoAs is an energy-dependent process and how this dephosphorylation is mediated warrants further investigations. It is plausible that dephosphorylation of acyl-CoAs and limited anaplerosis are involved in ischemic injuries to heart. Further investigations are warranted to examine the mechanisms of acyl-CoA dephosphorylation and how the dephosphorylation is possibly involved in ischemic injuries.

Myocardial ischemia-reperfusion (I/R) injury is a major cause of poor hemodynamic reconstitution outcomes after myocardial infarction or circulatory arrest. Currently, the search for effective therapeutic agents and tools is a focus of research in the field of myocardial I/R injury. Resveratrol (Res) has been extensively studied in recent years because of its good cardiovascular therapeutic effects, but its specific mechanism of action has not been fully elucidated. Therefore, the aim of this study was to investigate the mechanism of interaction between myocardial I/R injury and Res in vitro and in vivo. In our in vivo study, we used PI/TUNEL staining and western blotting to detect relevant necroptotic key molecules such as RIP1, RIP3 and p-MLKL/MLKL to observe myocardial necroptosis. The extent of myocardial injury was determined using hematoxylin and eosin (HE) staining and 2,3,5-triphenyltetrazolium chloride (TTC) staining as well as serum levels of CK-MB and LDH and echocardiography. In the in vitro study, cellular injury was assessed by CCK-8 and cell supernatant LDH levels. In addition, we used small interfering RNA (siRNA) transfection to knock down YAP, a key effector molecule of the Hippo pathway, to validate the molecular mechanism of action by which Res exerts myocardial protection. The localization of YAP in H9c2 cardiomyocytes was examined using immunofluorescence. Our data demonstrated that Res could ameliorate myocardial I/R-induced necroptosis by modulating the Hippo pathway, and that the beneficial effect of Res might be associated with nuclear translocation of the transcriptional regulator YAP.

Abnormal sulfide catabolism, especially the accumulation of hydrogen sulfide (H2S) during hypoxic or inflammatory stresses, is a major cause of redox imbalance-associated cardiac dysfunction. Polyhydroxynaphtoquinone echinochrome A (Ech-A), a natural pigment of marine origin found in the shells and needles of many species of sea urchins, is a potent antioxidant and inhibits acute myocardial ferroptosis after ischemia/reperfusion, but the chronic effect of Ech-A on heart failure is unknown. Reactive sulfur species (RSS), which include catenated sulfur atoms, have been revealed as true biomolecules with high redox reactivity required for intracellular energy metabolism and signal transduction. Here, we report that continuous intraperitoneal administration of Ech-A (2.0 mg/kg/day) prevents RSS catabolism-associated chronic heart failure after myocardial infarction (MI) in mice. Ech-A prevented left ventricular (LV) systolic dysfunction and structural remodeling after MI. Fluorescence imaging revealed that intracellular RSS level was reduced after MI, while H2S/HS- level was increased in LV myocardium, which was attenuated by Ech-A. This result indicates that Ech-A suppresses RSS catabolism to H2S/HS- in LV myocardium after MI. In addition, Ech-A reduced oxidative stress formation by MI. Ech-A suppressed RSS catabolism caused by hypoxia in neonatal rat cardiomyocytes and human iPS cell-derived cardiomyocytes. Ech-A also suppressed RSS catabolism caused by lipopolysaccharide stimulation in macrophages. Thus, Ech-A has the potential to improve chronic heart failure after MI, in part by preventing sulfide catabolism.

Cardiovascular disease (CVD) is defined as a class of disorders affecting the heart and blood vessels. Cardiomyocytes and endothelial cells play important roles in cardiac regeneration and heart repair. However, the proliferating capacity of cardiomyocytes is limited. To overcome this issue, mesenchymal stem cells (MSCs) have emerged as an alternative strategy for CVD therapy. MSCs can proliferate and differentiate (or trans-differentiate) into cardiomyocytes. Several in vitro and in vivo differentiation protocols have been used to obtain MSCs-derived cardiomyocytes. It was recently investigated that microRNAs (miRNAs) by targeting several signaling pathways, including STAT3, Wnt/β-catenin, Notch, and TBX5, play a crucial role in regulating cardiomyocytes' differentiation of MSCs. In this review, we focused on the role of miRNAs in the differentiation of MSCs into cardiomyocytes.

Acute myocardial infarction is an event of myocardial necrosis caused by unstable ischemic syndrome. Myocardial infarction (MI) occurs when blood stops flowing to the cardiac tissue or myocardium and the heart muscle gets damaged due to poor perfusion and reduced oxygen supply. Mitochondria can serve as the arbiter of cell fate in response to stress. Oxidative metabolism is the function of mitochondria within the cell. Cardiac cells being highly oxidative tissue generates about 90% of their energy through oxidative metabolism. In this review, we focused on the role of mitochondria in energy generation in myocytes as well as its consequences on heart cells causing cell damage. The role of mitochondrial dysfunction due to oxidative stress, production of reactive oxygen species, and anaerobic production of lactate as a failure of oxidative metabolism are also discussed.