Ischemic Heart Injury Research Articles

Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury.

Myocardial infarction initiates cardiac remodeling and is central to heart failure pathogenesis. Following myocardial ischemia-reperfusion injury, monocytes enter the heart and differentiate into diverse subpopulations of macrophages. Here we show that deletion of Hif1α, a hypoxia response transcription factor, in resident cardiac macrophages led to increased remodeling and overrepresentation of macrophages expressing arginase 1 (Arg1). Arg1+ macrophages displayed an inflammatory gene signature and may represent an intermediate state of monocyte differentiation. Lineage tracing of Arg1+ macrophages revealed a monocyte differentiation trajectory consisting of multiple transcriptionally distinct states. We further showed that deletion of Hif1α in resident cardiac macrophages resulted in arrested progression through this trajectory and accumulation of an inflammatory intermediate state marked by persistent Arg1 expression. Depletion of the Arg1+ trajectory accelerated cardiac remodeling following ischemic injury. Our findings unveil distinct trajectories of monocyte differentiation and identify hypoxia sensing as an important determinant of monocyte differentiation following myocardial infarction.

UCF101 Rescues against Diabetes-Evoked Cardiac Remodeling and Contractile Anomalies through AMPK-Mediated Induction of Mitophagy.

Diabetes mellitus is known to provoke devastating anomalies in myocardial structure and function while effective therapeutic regimen is still lacking. The selective protease inhibitor UCF101 (5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid) has been shown to fend off ischemic heart injury although its impact on diabetic cardiomyopathy remains elusive. Our present work was conducted to examine the effect of UCF101 on experimental diabetes-evoked cardiac geometric and functional abnormalities as well as mechanism involved. Adult mice were made diabetic using streptozotocin (STZ) while receiving UCF101 (7.15 mg/kg, i.p.) for 6 consecutive days. STZ evidently evoked cardiac hypertrophy, interstitial fibrosis, mitochondrial ultrastructural damage, oxidative stress, dampened autophagy (LC3B, Beclin1, elevated p62), mitophagy (FUNDC1 and Parkin with elevated TOM20), increased left ventricular (LV) end systolic diameter, dampened fractional shortening, ejection fraction, cardiomyocyte shortening capacity, velocities of shortening/relengthening, and rise in intracellular Ca2+ in conjunction with elongated diastole and intracellular Ca2+ removal, the responses were overtly reconciled by UCF101 with little effect from UCF101 itself. Levels of cell injury markers Omi/HtrA2, TNFα, and stress signaling (JNK, ERK, p38) were overtly enhanced along with compromised phosphorylation of cellular fuel AMPK (Thr172) and cell survival molecule GSK3β, as well as downregulated SERCA2a and elevated phospholamban, the effect was reversed by UCF101 (except for SERCA2a). AMPK knockout, pharmacological inhibition, mitophagy inhibitor liensinine and parkin knockout nullified UCF101-offered cardioprotection in diabetes. UCF101 reversed STZ-induced upregulation in the AMPK degrading enzymes PP2A and PP2C. These findings denote that UCF101 rescues diabetes-instigated alterations in cardiac structure and contraction, likely through AMPK-mediated regulation of mitophagy.

Sevoflurane Activates PI3K/AKT Signaling Pathway by Upregulating GDF11 Expression to Attenuate Ischemia/Reperfusion Injury in Cardiomyocytes.

Myocardial ischemia/reperfusion (I/R) injury stands as a primary contributor to ischemic heart disease. Sevoflurane (SEVO), a commonly used inhalation anesthetic, has been shown to exert a direct protective effect on ischemic heart injury. However, the specific mechanism by which it exerts the protective effect remains unclear. This study was designed to investigate the role of SEVO in myocardial I/R injury and its potential molecular mechanisms. Blood samples were collected from patients with acute myocardial infarction (AMI) (n = 20) and healthy volunteers (n = 20). The human cardiomyocytes AC16 models of I/R injury were induced by hypoxia/reoxygenation. The mRNA expression levels of growth differentiation factor 11 (GDF11) in the cells and blood were determined by reverse transcription quantitative real-time PCR (RT-qPCR). The cell proliferation was detected by Cell Counting Kit-8 (CCK-8). Enzyme-Linked Immunosorbent Assay (ELISA) was utilized to detect the levels of inflammatory factors interleukin (IL)-8, IL-1β and IL-6 in the cells. And biochemical assay kits were applied for the measurement of the activity of lactate dehydrogenase (LDH) and superoxide dismutase (SOD) as well as the malondialdehyde (MDA) level in the cells. Moreover, western blot was employed to evaluate the levels of the p-serine-threonine protein kinase (AKT), AKT, and phosphatidylinositol 3-kinase (PI3K), protein expression in the cells. The GDF11 expression was decreased in the blood of AMI patients and cardiomyocytes induced by I/R (p < 0.01). Besides, 1% SEVO was presented to promote cardiomyocyte proliferation, inhibit apoptosis, oxidative stress and inflammation, and activate the PI3K/AKT signaling pathway through up-regulation of GDF11 expression (p < 0.01). SEVO promotes proliferation and inhibits inflammatory response, apoptosis, and oxidative stress of I/R-treated cardiomyocytes by elevating GDF11 expression, thereby reducing myocardial I/R injury. Notably, the mechanism underlying the alleviation of the I/R injury may involve the activation of PI3K/AKT signaling pathway.

Correction to: C1q/Tumor Necrosis Factor-Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways.

Correction to: C1q/Tumor Necrosis Factor-Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways.

Overexpression of NDNF Improves the Cytoprotective Effects of Aged Human Bone Marrow Mesenchymal Stem Cells by Modulating Oxidative Stress and Apoptosis.

The therapeutic potential of autologous stem cell transplantation for heart repair diminishes in the elderly due to stem cell aging. Rejuvenating aged stem cells to enhance their protective effects on injured cardiomyocytes is crucial for aging patients with heart failure. In this study, we aimed to investigate whether neuron-derived neurotrophic factor (NDNF) over-expression improves the protective effect of aged stem cells for injured cardiomyocytes and explore the underlying mechanism. Human bone marrow was collected from both young and old patients, and bone marrow mesenchymal stem cells (BMSCs) were cultured. Lentivirus expression vectors carrying NDNF genes were used to transfect aged BMSCs. Fatal hypoxia-induced injury in H9C2 cells served as an in vitro ischemia model. The conditioned medium from different BMSC groups was applied to assess the beneficial effects on hypoxia-induced damage in myocardial H9C2 cells. Results revealed that the conditioned medium of NDNF over-expressed old BMSCs increased H9C2 cell viability and reduced oxidative stress and apoptosis levels under fatal hypoxia. NDNF over-expressed old BMSCs exhibited an antiapoptotic role by upregulating the antiapoptotic gene Bcl-2 and downregulating the proapoptotic genes Bax. Additionally, the protective effects were mediated through the elevation of phosphorylated AKT. Our data support the promise of NDNF as a potential target to enhance the protective effects of autologous aged BMSCs on ischemic cardiomyocytes and then improve the curative effects of stem cell for ischemic heart injury in aged patients.

Protective Effects of Trans-Chalcone on Myocardial Ischemia and Reperfusion Challenge through Targeting Phosphoinositide 3-kinase/Akt-inflammosome Interaction.

Ischemia-reperfusion (IR) injury remains a pivotal contributor to myocardial damage following acute coronary events and revascularization procedures. Phosphoinositide 3-kinase (PI3K), a key mediator of cell survival signaling, plays a central role in regulating inflammatory responses and cell death mechanisms. Trans-chalcone (Tch), a natural compound known for its anti-inflammatory activities, has shown promise in various disease models. The aim of the current study was to investigate the potential protective effects of Tch against myocardial injury induced by ischemia and reperfusion challenges by targeting the PI3K-inflammasome interaction. Experimental models utilizing male rats subjected to an in vivo model of IR injury and myocardial infarction were employed. Administration of Tch (100 μg/kg, intraperitoneally) significantly reduced myocardial injury, as indicated by limited infarct size and decreased levels of the myocardial enzyme troponin. Mechanistically, Tch upregulated PI3K expression, thereby inhibiting the activity of the NOD-like receptor protein 3 inflammasome followed by the activation of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. Moreover, it mitigated oxidative stress and suppressed vascular-intercellular adhesion molecules, contributing to its cardioprotective effects. The PI3K/Akt pathway inhibitor LY294002 considerably attenuated the beneficial effects of Tch. These findings highlight the therapeutic potential of Tch in ameliorating myocardial injury associated with IR insults through its modulation of the PI3K/Akt-inflammasome axis. The multifaceted mechanisms underlying its protective effects signify Tch as a promising candidate for further exploration in developing targeted therapies aimed at mitigating ischemic heart injury and improving clinical outcomes in cardiovascular diseases characterized by IR injury.

Cardioprotective Effect of Nano Gold Kalimag Injection via Inhibiting Oxidative Stress and Improving Myocardial Energy Metabolism in Ischemic Heart Injury Model

Background: Many people worldwide die from cardiovascular diseases. Myocardial ischemia can be induced by atherosclerosis, and the main factor responsible for atherosclerosis is the deposition of lipid peroxide in vessels. Therefore, atherogenesis may be prevented and treated at the cellular level by preventing oxidative stress using the properties of nanogold, magnesium and potassium. In this study, we have elucidated the cardioprotective effect of Nano Gold Kalimag injection (NGKM) in the ischemic heart injury model in rats. Methods: The ischemic heart injury models were made with adrenaline and pituitrin, and a few myocardial damage-related parameters of the models were observed after NGKM injection. After NGKM injection, the levels of lactate dehydrogenase (LDH), aspartate transamiase (AST), and creatine kinase (CK) in an ischemic heart injury model in rats were detected, and TTC staining and H&amp;E staining were performed. In addition, in the myocardial tissues of rats, superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), catalase, and Na+-K+-ATPase activity were measured, and lactate content and ATP content were measured. Results: NGKM can reduce the infarct area in the ischemic heart injury model and significantly lower LDH, AST, and CK levels. SOD, GSH-Px, and arterial tissue CAT levels significantly increased compared to the model, and MDA contents significantly decreased in myocardial tissue compared to the model group. In addition, myocardial tissue ATP content and Na+-K+-ATPase level in myocardial tissues significantly increased compared to the model group, and lactate content in myocardial tissue significantly decreased compared to the model group. Conclusions: Our findings suggest that NGKM injection has cardioprotective effects by inhibiting oxidative stress in an ischemic heart injury model in rats.

Abstract P3074: Alkylating Chemotherapy Reshapes The Immune Landscape Of The Heart

Cancer survivors typically have concomitant cardiac comorbidities and were exposed to various chemotherapeutic agents. Despite extensive investigation, we still have a poor understanding of how chemotherapy agents impact cardiac physiology and disease pathogenesis. Alkylating agents, for instance, carboplatin, are the backbone of many chemotherapy regimens and have been applied in cancer treatment for decades. Cardiac macrophages are the primary component of the cardiac immune landscape and play essential roles in homeostasis and disease. My data implied that alkylating drugs induced cell death of the reparative cardiac macrophages (CCR2-) through activating apoptosis and necroptosis. However, the pro-inflammatory subset (CCR2+) is not decreased. Intriguingly, the reparative macrophages recovered four weeks after the carboplatin treatment through proliferation but showed different gene expression profiles. To investigate the functional influence of these reshaped macrophages in heart diseases, I established a hypertensive heart injury model and an ischemic heart injury model using carboplatin-exposed mice. Interestingly, these mice showed less fibrosis and smaller infarct size. Further, I used CD169-DTR mice that allow selective ablation of CCR2- macrophages. The attenuated remodeling phenotype is abolished without the reshaped CCR2- macrophages. Moreover, the type I interferon signaling in CCR2- macrophage is significantly upregulated in carboplatin-exposed mice upon hypertensive injury. Using neutralizing antibodies to block the IFN-I signaling, I found heart remodeling in carboplatin-treated mice became more advanced. Together, my study revealed that alkylating chemotherapy reshaped the immune landscape of the heart and mitigated adverse heart remodeling by activating the IFN-I signaling pathway in cardiac resident macrophages. These findings highlighted the role of CCR2- macrophages and the IFN-I signaling in the long-term cardiac effects of alkylating chemotherapy.

EGCG attenuated acute myocardial infarction by inhibiting ferroptosis via miR-450b-5p/ACSL4 axis

BackgroundEpigallocatechin gallate (EGCG) has multiple biological effects such as anti-tumor multiple drug resistance, antioxidation and anti-inflammatory properties. Ferroptosis is the main driving factor of ischemic heart injury, thus inhibiting ferroptosis may prove to be an effective treatment strategy for cardiovascular diseases. However, the role of EGCG on ferroptosis in ischemic myocardium and underlying mechanisms remain uncertain. PurposeThis study was aimed to investigate the effects and potential mechanisms of EGCG on myocardial ischemic-induced ferroptosis both in vitro and in vivo. MethodsCardiomyocyte hypoxia model and mouse acute myocardial infarction (AMI) model were established in vitro and in vivo. MiR-450b-5p and ACSL4 silencing or overexpression plasmids were transfected, with or without EGCG pretreatment. Cell viability was determined by the CCK-8 assay. Hematoxylin and eosin (HE) staining and transmission electron microscopy (TEM) were used to evaluate the morphologic alterations. TTC staining was used to observe the infarction area, and echocardiography was adopted to appraise the heart function. Using flow cytometry, the presence of reactive oxygen species (ROS) was assessed. The content of cardiac troponin I (cTn I), glutathione (GSH), malondialdehyde (MDA), divalent iron ions (Fe2+) and superoxide dismutase (SOD) were detected using reagent kits. A luciferase activity assay was performed to assess the binding ability of miR-450b-5p to ACSL4. Expressions of related genes and proteins were measured by RT-qPCR and western blotting respectively. ResultsEGCG attenuated AMI-induced ferroptosis and improved myocardial ischemia injury, which was associated with reducing iron deposition and cTn I, inhibition of lipid peroxidation, decreasing TFR1 and ACSL4, and upregulating SLC7A11, FTH1 and GPX4. Meanwhile, EGCG pretreatment increased miR-450b-5p expression in ischemic myocardium. Further researches discovered that knockdown of miR-450b-5p partially compromised EGCG-generated protective effect in hypoxia HL-1 cells, while combination with miR-450b-5p mimic could strengthen the potency of EGCG on ischemic myocardium. The dual-luciferase test demonstrated that miR-450b-5p has binding to ACSL4. Furthermore, silencing of ACSL4 synergistically increased the cardioprotective effect of EGCG. More significantly, EGCG treatment regulated the ferroptosis-related proteins expression via miR-450b-5p/ACSL4 axis. ConclusionIn summary, the present study evidently demonstrated that EGCG attenuates myocardial ischemia injury by targeting ferroptosis. Our work revealed the role of miR-450b-5p/ACSL4 axis in AMI for the first time. Further, it also elucidated the molecular mechanisms of EGCG on inhibiting ferroptosis greatly depend on the miR-450b-5p/ACSL4 axis, suggesting that EGCG may act as a novel anti-ferroptosis agent and exert a therapeutic role in AMI.

Exposure to Stress Alters Cardiac Gene Expression and Exacerbates Myocardial Ischemic Injury in the Female Murine Heart.

Mental stress is a risk factor for myocardial infarction in women. The central hypothesis of this study is that restraint stress induces sex-specific changes in gene expression in the heart, which leads to an intensified response to ischemia/reperfusion injury due to the development of a pro-oxidative environment in female hearts. We challenged male and female C57BL/6 mice in a restraint stress model to mimic the effects of mental stress. Exposure to restraint stress led to sex differences in the expression of genes involved in cardiac hypertrophy, inflammation, and iron-dependent cell death (ferroptosis). Among those genes, we identified tumor protein p53 and cyclin-dependent kinase inhibitor 1A (p21), which have established controversial roles in ferroptosis. The exacerbated response to I/R injury in restraint-stressed females correlated with downregulation of p53 and nuclear factor erythroid 2-related factor 2 (Nrf2, a master regulator of the antioxidant response system-ARE). S-female hearts also showed increased superoxide levels, lipid peroxidation, and prostaglandin-endoperoxide synthase 2 (Ptgs2) expression (a hallmark of ferroptosis) compared with those of their male counterparts. Our study is the first to test the sex-specific impact of restraint stress on the heart in the setting of I/R and its outcome.

MORN4 protects cardiomyocytes against ischemic injury via MFN2-mediated mitochondrial dynamics and mitophagy

The imbalance of mitochondrial fission and fusion dynamics causes ischemic cardiomyocyte apoptosis and heart injury by affecting mitophagy. Regulation of mitochondrial dynamics is an important therapeutic strategy for ischemic heart diseases. Considering the important roles of MORN motifs in heart diseases and chloroplast fission, we aimed to investigate the possible role of MORN repeat-containing protein 4 (MORN4) in the progression of myocardial infarction (MI), ischemic cardiomyocyte apoptosis, mitochondrial dynamics, and mitophagy. We found that in the MI mouse, MORN4 knockdown remarkably accelerated cardiac injury and fibrosis with deteriorating cardiac dysfunction. Sphingosylphosphorylcholine (SPC) alleviated ischemic cardiomyocyte apoptosis and heart injury through increased level of MORN4, indicating a vital function of MORN4 in heart with SPC used to clarify the molecular mechanisms underlying the functions of MORN4. Mechanistically, we found that MORN4 directly binds to MFN2 and promotes the phosphorylation of MFN2 S442 through Rho-associated protein kinase 2 (ROCK2), which mediates beneficial mitophagy induced by mitochondrial dynamics, while SPC promoted the binding of MORN4 and MFN2 and the process. Taken together, our data reveal a new perspective role of MORN4 in ischemic heart injury, and report that SPC could regulate myocardial mitochondrial homeostasis by activating the MORN4-MFN2 axis during the ischemic situation, this finding provides novel targets for improving myocardial ischemia tolerance and rescue of acute myocardial infarction.

CSF2RB overexpression promotes the protective effects of mesenchymal stromal cells against ischemic heart injury.

Aims: The invasive intramyocardial injection of mesenchymal stromal cells (MSCs) allows for limited repeat injections and shows poor therapeutic efficacy against ischemic heart failure. Intravenous injection is an alternative method because this route allows for repeated, noninvasive, and easy delivery. However, the lack of targeting of MSCs hinders the ability of these cells to accumulate in the ischemic area after intravenous injections. We investigated whether and how the overexpression of colony-stimulating factor 2 receptor beta subunit (CSF2RB) may regulate the cardiac homing of MSCs and their cardioprotective effects against ischemic heart failure. Methods and Results: Adult mice were subjected to myocardial ischemia/reperfusion (MI/R) or sham operations. We observed significantly higher CSF2 protein expression and secretion by the ischemic heart from 1 day to 2 weeks after MI/R. Mouse adipose tissue-derived MSCs (ADSCs) were infected with adenovirus harboring CSF2RB or control adenovirus. Enhanced green fluorescent protein (EGFP)-labeled ADSCs were intravenously injected into MI/R mice every three days for a total of 7 times. Compared with ADSCs infected with control adenovirus, intravenously delivered ADSCs overexpressing CSF2RB exhibited markedly increased cardiac homing. Histological analysis revealed that CSF2RB overexpression significantly enhanced the ADSC-mediated proangiogenic, antiapoptotic, and antifibrotic effects. More importantly, ADSCs overexpressing CSF2RB significantly increased the left ventricular ejection fraction and cardiac contractility/relaxation in MI/R mice. In vitro experiments demonstrated that CSF2RB overexpression increases the migratory capacity and reduces the hypoxia/reoxygenation-induced apoptosis of ADSCs. We identified STAT5 phosphorylation as the key mechanism underlying the effects of CSF2RB on promoting ADSC migration and inhibiting ADSC apoptosis. RNA sequencing followed by cause-effect analysis revealed that CSF2RB overexpression increases the expression of the ubiquitin ligase RNF4. Coimmunoprecipitation and coimmunostaining experiments showed that RNF4 binds to phosphorylated STAT5. RNF4 knockdown reduced STAT5 phosphorylation as well as the antiapoptotic and promigratory actions of ADSCs overexpressing CSF2RB. Conclusions: We demonstrate for the first time that CSF2RB overexpression optimizes the efficacy of intravenously delivered MSCs in the treatment of ischemic heart injury by increasing the response of the MSCs to a CSF2 gradient and CSF2RB-dependent STAT5/RNF4 activation.

Прогноз пацієнтів із гострим інфарктом міокарда з підйомом сегмента ST після проведення первинного черезшкірного коронарного втручання

Myocardial infarction claims million lives on the planet each year. Ischemic heart injury is diagnosed with increasing incidence among younger people of working age, posing significant medical and social problem. Percutaneous coronary interventions (PCI) are the primary treatment for ST-segment elevation myocardial infarction (STEMI). The aim of the study was to optimize the prognosis of acute STEMI after primary PCI. Materials and methods. The study included 98 patients with STEMI who were undergoing primary PCI. As a part of revascularization procedure, a manual thromboaspiration was performed for each patient. Thrombotic material was obtained at a volume sufficient for histological analysis with further macro- and microscopic examination. Prognosis was assessed by the probability of occurrence of major coronary events, such as death, myocardial infarction, repeated revascularization or reappearance of angina. In order to single out the factors that, when combined, have a reliable influence on the prognosis, a step-by-step method of logistic regression with forward selection was used. To assess the level of plausibility of the obtained model, a pseudo R-square Nagelkerkes analysis, an analogue of R-square for linear regression, was performed. The results. During two years of follow-up, major coronary events occurred in 34 patients (34.69%). After analysis of the obtained data, four characteristics of thrombi were separated, which, when combined, had an impact on the development of the end-point. These were old thrombi, the presence of microchannels, inflammatory infiltration, and macroscopically mixed thrombi. The resulting formula was as follows: Z = 0.5•V2 – 0.04•V1 – 0.1•V3 + 1.77•V4 – 1.51, where V1 = old thrombus, V2 = presence of microchannels, V3 = inflammatory infiltration, V4 = macroscopically mixed thrombus. Conclusions. Analysis of the morphological characteristics of intracoronary thrombi allowed assessing the long-term prognosis in patients with STEMI. Article received: 28.11.2022

Chick early amniotic fluid component improves heart function and protects against inflammation after myocardial infarction in mice.

Myocardial infarction (MI) is the major cause of mortality around the world. We recently demonstrated that chick early amniotic fluid (ceAF) can effectively rescue ischemic heart injury, indicating that it has a therapeutic function in MI. However, its functional components and the underlying mechanisms remain to be clarified. Here, we demonstrated that a fraction of ceAF, peak 8 (P8), had a protective effect on acute MI. P8 significantly decreased cardiomyocyte cross-sectional areas and cardiomyocyte apoptosis in MI mice. Using a human embryonic stem cell-derived cardiomyocyte model, which was subjected to hypoxia and reoxygenation, mimicking MI state, we found that P8 treatment reduced apoptosis and reversed myocardial contractility. Mechanistically, P8 improved cardiac function by inhibiting NF-κB signaling and downregulating inflammatory cytokine expression. Using mass spectrometry, we identified that guanosine and deoxynucleoside were the main functional components of P8 that suppressed the inflammatory response in human embryonic stem cell-derived cardiomyocytes. Collectively, our data suggest that specific components from ceAF are promising therapeutic agents for ischemic heart injury and could be a potential supplement to current medications for MI.

Exosomes derived from pericardial adipose tissues attenuate cardiac remodeling following myocardial infarction by Adipsin-regulated iron homeostasis.

As a vital adipokine, Adipsin is closely associated with cardiovascular risks. Nevertheless, its role in the onset and development of cardiovascular diseases remains elusive. This study was designed to examine the effect of Adipsin on survival, cardiac dysfunction and adverse remodeling in the face of myocardial infarction (MI) injury. In vitro experiments were conducted to evaluate the effects of Adipsin on cardiomyocyte function in the face of hypoxic challenge and the mechanisms involved. Our results showed that Adipsin dramatically altered expression of proteins associated with iron metabolism and ferroptosis. In vivo results demonstrated that Adipsin upregulated levels of Ferritin Heavy Chain (FTH) while downregulating that of Transferrin Receptor (TFRC) in peri-infarct regions 1 month following MI. Adipsin also relieved post-MI-associated lipid oxidative stress as evidenced by decreased expression of COX2 and increased GPX4 level. Co-immunoprecipitation and immunofluorescence imaging prove a direct interaction between Adipsin and IRP2. As expected, cardioprotection provided by Adipsin depends on the key molecule of IRP2. These findings revealed that Adipsin could be efficiently delivered to the heart by exosomes derived from pericardial adipose tissues. In addition, Adipsin interacted with IRP2 to protect cardiomyocytes against ferroptosis and maintain iron homeostasis. Therefore, Adipsin-overexpressed exosomes derived from pericardial adipose tissues may be a promising therapeutic strategy to prevent adverse cardiac remodeling following ischemic heart injury.

Aldehyde dehydrogenase 2 and arrhythmogenesis.

Cardiac arrhythmia is a common cardiovascular disease that leads to considerable economic burdens and significant global public health challenges. Despite the remarkable progress made in recent decades, antiarrhythmic therapy remains suboptimal. Aldehyde dehydrogenase 2 (ALDH2), a critical detoxifying enzyme, catalyzes toxic aldehydes and protects individuals from damage caused by oxidative stress. Accumulating evidence has demonstrated that ALDH2 activation has potential antiarrhythmic benefits. The correlation between ALDH2 deficiency and arrhythmogenesis has been widely recognized. In this review, we summarize recent research on the potential role of ALDH2 activation and antiarrhythmic protection, as well as the role played by the ALDH2∗2 polymorphism (rs671) in promoting arrhythmic risk. Additionally, we discuss important new findings illustrating the use of ALDH2 activators, which may prove to be promising antiarrhythmic therapy agents.

Hypoxic preconditioned aged BMSCs accelerates MI injury repair by modulating inflammation, oxidative stress and apoptosis

The benefits of autologous cell therapy for cardiac repair are diminished in aged individuals due to the limited quality and poor tolerance of aged stem cells in the ischemic micro-environment. The safe and efficient methods to improve the therapeutic effect of aged stem cells are needed to treat the increasing number of aged patients with cardiac diseases. In the present study, we aimed to determine whether hypoxic preconditioning can improve the therapeutic effect of aged stem cells even if the responsiveness of aged MSCs is poor, and to seek the underlying mechanism. Using a murine model of MI, our results showed that hypoxic preconditioning promoted the therapeutic effect of aged BMSCs, which was expressed in improved cardiac function, decreased scar size and alleviated cardiac remodeling in vivo. This in vivo effect of hypoxic preconditioned aged BMSCs was associated with alleviated inflammation, oxidative stress and apoptosis in infarcted heart. In vitro studies confirmed that hypoxic preconditioned aged BMSCs exert cytoprotective impacts on H9C2 cells against lethal hypoxia injury via attenuating oxidative stress and apoptosis. Our data support the promise of hypoxic preconditioning as a potential strategy to improve autologous stem cell therapy for ischemic heart injury in aged individuals.

Inhibition of Nitrosative Stress Attenuates Myocardial Injury and Improves Outcomes after Cardiac Arrest and Resuscitation.

Nitrosative stress is widely involved in cell injury via inducing the nitration modification of a variety of proteins. This study aimed to investigate whether inhibition of nitrosative stress attenuated myocardial injury and improved outcomes in a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Adult male Wistar rats were subjected to asphyxia-induced cardiac arrest and subsequently resuscitation. One minute after return of spontaneous circulation (ROSC), rats were randomized and administered the nitrosative stress inhibitor, FeTMPyP (1 or 3 mg/kg), or normal saline as a placebo. 3-Nitrotyrosine (3-NT), mean arterial pressure (MAP), heart rate (HR), mortality, electrocardiogram (ECG), left ventricular ejection fraction (EF) and fractional shortening (FS), and levels of myocardial apoptosis were evaluated. The concentrations of lactate, creatine kinase MB isoenzyme (CK-MB), and angiotensin II (Ang II), were measured in blood samples. 3-NT level was significantly increased in the heart after ROSC. Administration of FeTMPyP (1 or 3 mg/kg) attenuated the increase of 3-NT in the myocardium. Inhibition of nitrosative stress improved survival and attenuated CA/CPR-induced reperfusion injury by maintaining the stability of MAP and HR, and reducing the accumulation of lactic acid. Post-cardiac arrest rats had higher serum CK-MB and Ang II than healthy rats, while EF and FS were lower in healthy rats. Inhibition of nitrosative stress not only alleviated ischemic heart injury but also reduced the occurrence of CA/CPR-induced of arrhythmias. Moreover, nitrosative stress mediated the upregulation of Cleaved caspase-3 and downregulation Bcl-2, which was abolished by FeTMPyP. Inhibition of nitrosative stress is a novel molecular target to alleviate myocardial injury and improve outcomes in a rat model of CA/CPR.

A cardioimmunologist's toolkit: genetic tools to dissect immune cells in cardiac disease.

Cardioimmunology is a field that encompasses the immune cells and pathways that modulate cardiac function in homeostasis and regulate the temporal balance between tissue injury and repair in disease. Over the past two decades, genetic fate mapping and high-dimensional sequencing techniques have defined increasing functional heterogeneity of innate and adaptive immune cell populations in the heart and other organs, revealing a complexity not previously appreciated and challenging established frameworks for the immune system. Given these rapid advances, understanding how to use these tools has become crucial. However, cardiovascular biologists without immunological expertise might not be aware of the strengths and caveats of immune-related tools and how they can be applied to examine the pathogenesis of myocardial diseases. In this Review, we guide readers through case-based examples to demonstrate how tool selection can affect data quality and interpretation and we provide critical analysis of the experimental tools that are currently available, focusing on their use in models of ischaemic heart injury and heart failure. The goal is to increase the use of relevant immunological tools and strategies among cardiovascular researchers to improve the precision, translatability and consistency of future studies of immune cells in cardiac disease.

Insight into the Role of the PI3K/Akt Pathway in Ischemic Injury and Post-Infarct Left Ventricular Remodeling in Normal and Diabetic Heart.

Despite the significant decline in mortality, cardiovascular diseases are still the leading cause of death worldwide. Among them, myocardial infarction (MI) seems to be the most important. A further decline in the death rate may be achieved by the introduction of molecularly targeted drugs. It seems that the components of the PI3K/Akt signaling pathway are good candidates for this. The PI3K/Akt pathway plays a key role in the regulation of the growth and survival of cells, such as cardiomyocytes. In addition, it has been shown that the activation of the PI3K/Akt pathway results in the alleviation of the negative post-infarct changes in the myocardium and is impaired in the state of diabetes. In this article, the role of this pathway was described in each step of ischemia and subsequent left ventricular remodeling. In addition, we point out the most promising substances which need more investigation before introduction into clinical practice. Moreover, we present the impact of diabetes and widely used cardiac and antidiabetic drugs on the PI3K/Akt pathway and discuss the molecular mechanism of its effects on myocardial ischemia and left ventricular remodeling.