Heart Injury Research Articles

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.

Multiorgan recovery in a cadaver body using mild hypothermic ECMO treatment in a murine model

BackgroundTransplant candidates on the waiting list are increasingly challenged by the lack of organs. Most of the organs can only be kept viable within very limited timeframes (e.g., mere 4–6 h for heart and lungs exposed to refrigeration temperatures ex vivo). Donation after circulatory death (DCD) using extracorporeal membrane oxygenation (ECMO) can significantly enlarge the donor pool, organ yield per donor, and shelf life. Nevertheless, clinical attempts to recover organs for transplantation after uncontrolled DCD are extremely complex and hardly reproducible. Therefore, as a preliminary strategy to fulfill this task, experimental protocols using feasible animal models are highly warranted. The primary aim of the study was to develop a model of ECMO-based cadaver organ recovery in mice. Our model mimics uncontrolled organ donation after an “out-of-hospital” sudden unexpected death with subsequent “in-hospital” cadaver management post-mortem. The secondary aim was to assess blood gas parameters, cardiac activity as well as overall organ state. The study protocol included post-mortem heparin–streptokinase administration 10 min after confirmed death induced by cervical dislocation under full anesthesia. After cannulation, veno-arterial ECMO (V–A ECMO) was started 1 h after death and continued for 2 h under mild hypothermic conditions followed by organ harvest. Pressure- and flow-controlled oxygenated blood-based reperfusion of a cadaver body was accompanied by blood gas analysis (BGA), electrocardiography, and histological evaluation of ischemia–reperfusion injury. For the first time, we designed and implemented, a not yet reported, miniaturized murine hemodialysis circuit for the treatment of severe hyperkalemia and metabolic acidosis post-mortem.ResultsBGA parameters confirmed profound ischemia typical for cadavers and incompatible with normal physiology, including extremely low blood pH, profound negative base excess, and enormously high levels of lactate. Two hours after ECMO implantation, blood pH values of a cadaver body restored from < 6.5 to 7.3 ± 0.05, pCO2 was lowered from > 130 to 41.7 ± 10.5 mmHg, sO2, base excess, and HCO3 were all elevated from below detection thresholds to 99.5 ± 0.6%, − 4 ± 6.2 and 22.0 ± 6.0 mmol/L, respectively (Student T test, p < 0.05). A substantial decrease in hyperlactatemia (from > 20 to 10.5 ± 1.7 mmol/L) and hyperkalemia (from > 9 to 6.9 ± 1.0 mmol/L) was observed when hemodialysis was implemented. On balance, the first signs of regained heart activity appeared on average 10 min after ECMO initiation without cardioplegia or any inotropic and vasopressor support. This was followed by restoration of myocardial contractility with a heart rate of up to 200 beats per minute (bpm) as detected by an electrocardiogram (ECG). Histological examinations revealed no evidence of heart injury 3 h post-mortem, whereas shock-specific morphological changes relevant to acute death and consequent cardiac/circulatory arrest were observed in the lungs, liver, and kidney of both control and ECMO-treated cadaver mice.ConclusionsThus, our model represents a promising approach to facilitate studying perspectives of cadaveric multiorgan recovery for transplantation. Moreover, it opens new possibilities for cadaver organ treatment to extend and potentiate donation and, hence, contribute to solving the organ shortage dilemma.

Eleutheroside E from pre-treatment of Acanthopanax senticosus (Rupr.etMaxim.) Harms ameliorates high-altitude-induced heart injury by regulating NLRP3 inflammasome-mediated pyroptosis via NLRP3/caspase-1 pathway.

Eleutheroside E, a major natural bioactive compound in Acanthopanax senticosus (Rupr.etMaxim.) Harms, possesses anti-oxidative, anti-fatigue, anti-inflammatory, anti-bacterial and immunoregulatory effects. High-altitude hypobaric hypoxia affects blood flow and oxygen utilisation, resulting in severe heart injury that cannot be reversed, thereby eventually causing or exacerbating high-altitude heart disease and heart failure. The purpose of this study was to determine the cardioprotective effects of eleutheroside E against high-altitude-induced heart injury (HAHI), and to study the mechanisms by which this happens. A hypobaric hypoxia chamber was used in the study to simulate hypobaric hypoxia at the high altitude of 6000m. 42 male rats were randomly assigned to 6 equal groups and pre-treated with saline, eleutheroside E 100mg/kg, eleutheroside E 50mg/kg, or nigericin 4mg/kg. Eleutheroside E exhibited significant dose-dependent effects on a rat model of HAHI by suppressing inflammation and pyroptosis. Eleutheroside E downregulated the expressions of brain natriuretic peptide (BNP), creatine kinase isoenzymes (CK-MB) and lactic dehydrogenase (LDH). Moreover, The ECG also showed eleutheroside E improved the changes in QT interval, corrected QT interval, QRS interval and heart rate. Eleutheroside E remarkably suppressed the expressions of NLRP3/caspase-1-related proteins and pro-inflammatory factors in heart tissue of the model rats. Nigericin, known as an agonist of NLRP3 inflammasome-mediated pyroptosis, reversed the effects of eleutheroside E. Eleutheroside E prevented HAHI and inhibited inflammation and pyroptosis via the NLRP3/caspase-1 signalling pathway. Taken together, eleutheroside E is a prospective, effective, safe and inexpensive agent that can be used to treat HAHI.

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.

Transmembrane protein 117 knockdown protects against angiotensin-II-induced cardiac hypertrophy

Mitochondrial dysfunction plays a critical role in the pathogenesis of pathological cardiac hypertrophy. Transmembrane protein 117 modulate mitochondrial membrane potential that may be involved in the regulation of oxidative stress and mitochondrial function. However, its role in the development of angiotensin II (Ang-II)-induced cardiac hypertrophy is unclear. Cardiac-specific TMEM117-knockout and control mice were subjected to cardiac hypertrophy induced by Ang-II infusion. Small-interfering RNAs against TMEM117 or adenovirus-based plasmids encoding TMEM117 were delivered into left ventricles of mice or incubated with neonatal murine ventricular myocytes (NMVMs) before Ang-II stimulation. We found that TMEM117 was upregulated in hypertrophic hearts and cardiomyocytes and TMEM117 deficiency attenuated Ang-II-induced cardiac hypertrophy in vivo. Consistently, the in vitro data demonstrated that Ang-II-induced cardiomyocyte hypertrophy significantly alleviated by TMEM117 knockdown. Conversely, overexpression of TMEM117 exacerbated cardiac hypertrophy and dysfunction. An Ang II-induced increase in cardiac (cardiomyocyte) oxidative stress was alleviated by cardiac-specific knockout (knockdown) of TMEM117 and was worsened by TMEM117 supplementation (overexpression). In addition, TMEM117 knockout decreased endoplasmic reticulum stress induced by Ang-II, which was reversed by TMEM117 supplementation. Furthermore, TMEM117 deficiency mitigated mitochondrial injury in hypertrophic hearts and cardiomyocyte, which was abolished by TMEM117 supplementation (overexpression). Taken together, these findings suggest that upregulation of TMEM117 contributes to the development of cardiac hypertrophy and the downregulation of TMEM117 may be a new therapeutic strategy for the prevention and treatment of cardiac hypertrophy.

Coronary Ischemia Study for Patients Admitted to Damascus Hospital Under the Age of Forty Years

Introduction: Coronary artery disease is a common heart condition that involves the formation of atherosclerotic plaques in the lumen of blood vessels. This study describes the evaluation, diagnosis, and management of coronary artery disease and highlights the role of the health care team in the evaluation and treatment of patients with this condition. Materials And Methodology: A cross-sectional study targeting 200 patients under the age of 40 attending a Damascus hospital with coronary ischemia. Results: We extracted, by interpreting the results of the descriptive statistics and applying the Chi-Square tests and ANOVA, many interesting results regarding the assessment of coronary heart injury in patients admitted from the age groups younger than 40, and we found a concentration of infection in the ages. At older ages, as it develops in adults younger than 40 years old. Recommendations: One of the most important recommendations of our study is to ascertain the reasons for the absence of this relationship in the age groups younger than 40 years, and to search for other non-traditional risk factors that may be useful in determining the causality behind the increasing incidence of coronary heart diseases in unusually young age groups.

Dapagliflozin ameliorates sepsis-induced heart injury by inhibiting cardiomyocyte apoptosis and electrical remodeling through the PI3K/Akt pathway

BackgroundSepsis-induced heart injury is one of the leading causes of circulation disorders worldwide. Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor mainly used for controlling blood glucose, has been shown to exert a protective effect on cardiomyocytes. However, the protective effect of dapagliflozin against sepsis-induced cardiac injury and the underlying mechanism needs to be studied. AimThis study aims to investigate the effect of dapagliflozin on sepsis-induced cardiomyopathy and the potential mechanisms involved. MethodsThe rat model of sepsis was constructed by intraperitoneal injection of lipopolysaccharide. Echocardiography and electrophysiological studies were performed to detect changes in cardiac function and electrical activity. Cardiac pathological alternation and cardiomyocyte apoptosis were measured by H&E staining, serological analysis, immunohistochemical, immunofluorescence, and TUNEL assays. Western blot and qRT-PCR were performed to elucidate the underlying mechanism of dapagliflozin. Additionally, corresponding experiments in H9c2 cells were performed to further validate the mechanisms in vitro. ResultsDapagliflozin improved cardiac dysfunction and reduced the susceptibility to ventricular arrhythmias in sepsis rats by ameliorating cardiac inflammation, suppressing cardiomyocyte apoptosis, and alleviating ventricular electrical remodeling. The PI3K/Akt signaling pathway inhibitor inhibited the anti-apoptotic effect of dapagliflozin, indicating that the protective effect was related to the activation of the PI3K/Akt pathway. ConclusionDapagliflozin ameliorated sepsis-induced cardiac injury by suppressing electrical remodeling and cardiomyocyte apoptosis, which could be attributed to the PI3K/Akt pathway.

Protective effects of limb remote ischemic per-conditioning on the heart injury induced by renal ischemic-reperfusion through the interaction of the apelin with the RAS/iNOS pathway.

Remote ischemic conditioning upregulates endogenous protective pathways in response to ischemia-reperfusion injury. This study tested the hypothesis that limb remote ischemic per- conditioning (RIPerC) exerts cardioprotective effects via the renin-angiotensin system (RAS)/inducible nitric oxide synthase (iNOS)/apelin pathway. Renal ischemia-reperfusion injury (I/R) was induced by bilateral occlusion of the renal pedicles for 60 minutes, followed by 24 hours of reperfusion; sham-operated rats served as controls. RIPerC was induced by four cycles (5 minutes) of limb ischemia-reperfusion along with bilateral renal ischemia. The functional disturbance was evaluated by renal (BUN and creatinine) and cardiac (troponin I and lactate dehydrogenase) injury biomarkers. Renal I/R injury increased renal and cardiac injury biomarkers that were reduced in the RIPerC group. Histopathological findings of the kidney and heart were also suggestive of amelioration injury-induced changes in the RIPerC group. Assessment of cardiac electrophysiology revealed that RIPerC ameliorated the decline in P wave duration without significantly affecting other cardiac electrophysiological changes. Further, renal I/R injury increased the plasma (322.40±34.01 IU/L), renal (8.27±1.10 mIU/mg of Protein), and cardiac (68.28±10.28 mIU/mg of protein) angiotensin-converting enzyme (ACE) activities in association with elevations in the plasma and urine nitrite (25.47±2.01 & 16.62±3.05 μmol/L) and nitrate (15.47±1.33 & 5.01±0.96 μmol/L) levels; these changes were reversed by RIPerC. Further, renal ischemia-reperfusion injury significantly (P=0.047) decreased the renal (but not cardiac) apelin mRNA expression, while renal and cardiac ACE2 (P<0.05) and iNOS (P=0.043) mRNA expressions were significantly increased compared to the sham group; these effects were largely reversed by RIPerC. Our results indicated that RIPerC protects the heart against renal ischemia- reperfusion injury, likely via interaction of the apelin with the RAS/iNOS pathway.

Unleashing the power of formyl peptide receptor 2 in cardiovascular disease

N-formyl peptide receptors (FPRs) are seven-transmembrane, G protein-coupled receptors with a wide distribution in immune and non-immune cells, recognizing N-formyl peptides from bacterial and mitochondrial origin and several endogenous signals. Three FPRs have been identified in humans: FPR1, FPR2, and FPR3. Most FPR ligands can activate a pro-inflammatory response, while a limited group of FPR agonists can elicit anti-inflammatory and homeostatic responses. Annexin A1 (AnxA1), a glucocorticoid-induced protein, its N-terminal peptide Ac2-26, and lipoxin A4 (LXA4), a lipoxygenase-derived eicosanoid mediator, exert significant immunomodulatory effects by interacting with FPR2 and/or FPR1. The ability of FPRs to recognize both ligands with pro-inflammatory or inflammation-resolving properties places them in a crucial position in the balance between activation against harmful events and maintaince of tissue integrity. A new field of investigation focused on the role of FPRs in the setting of heart injury. FPRs are expressed on cardiac macrophages, which are the predominant immune cells in the myocardium and play a key role in heart diseases. Several endogenous (AnxA1, LXA4) and synthetic compounds (compound 43, BMS-986235) reduced infarct size and promoted the resolution of inflammation via the activation of FPR2 on cardiac macrophages. Further studies should evaluate FPR2 role in other cardiovascular disorders.

Peficitinib ameliorates doxorubicin-induced cardiotoxicity by suppressing cellular senescence and enhances its antitumor activity

Irreversible cardiotoxicity limits the clinical applications of doxorubicin (DOX). Cardiotoxicity can be detected early using clinical assessment; however, effective preventive measures are still lacking. Peficitinib (ASP015K), a JAK (Janus kinase) inhibitor, is a potent anti-inflammatory agent in autoimmune diseases. Nevertheless, little research has been conducted on anti-ageing and anti-tumour therapies. In this study, we investigated whether ASP015K could attenuate DOX-induced cardiotoxicity through its anti-ageing effects and whether it would affect the tumour treatment effect of DOX by establishing senescence, acute heart injury, and xenograft models. We observed that ASP015K could antagonise the senescence induced by various factors, including hydrogen peroxide and DOX. In addition, ASP015K treatment significantly alleviated cardiac function damage, histopathological deterioration, myocardial fibrosis, and oxidative damage in acute injury mouse models. ASP015K enhanced the sensitivity of tumour cells to DOX therapy and significantly slowed down the tumour growth rate and tumour volume in the xenograft mouse model. Therefore, ASP015K is expected to be developed as a potential cardioprotective agent to prevent or reduce the cardiotoxic side effects of anthracyclines in chemotherapy.

Cyclovirobuxine D pretreatment ameliorates septic heart injury through mitigation of ferroptosis.

Myocardial dysfunction is a frequent complication in patients with severe sepsis. However, effective drugs for the prevention of myocardial dysfunction and the molecular mechanisms of the disease remain elusive. The present study demonstrated that Cyclovirobuxine D (CVB-D) could improve cardiac dysfunction in a cecal ligation and puncture (CLP) model in rodents and in a lipopolysaccharide (LPS) model in vitro. Echocardiography and histopathological examination were used to detect changes in cardiac structure and function. Kits were used to detect indicators of cardiac injury, transmission electron microscopy to detect structural changes in mitochondria and reverse transcription-quantitative PCR to detect prostaglandin-endoperoxide synthase 2 and hamp expression levels. L-Glutathione and malondialdehyde levels and superoxide dismutase activity were measured using kits. Cell viability was measured with the Cell Counting Kit-8. Iron metabolism-related proteins, inflammatory factor levels and related pathway proteins were detected using western blot analysis. Changes in L-type calcium currents were detected by membrane clamp, and contractility of cardiomyocytes was measured by Ion Optix. CVB-D attenuated CLP-induced cardiac malfunction in septic rats, with changes observed in myocardial pathological structure, creatine kinase isoenzyme (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin I (cTnI). CVB-D attenuated sepsis-induced lipid peroxidation and iron overload. In addition, CVB-D decreased the expression of CK-MB, LDH and cTnI, suppressed oxidative stress index levels and reduced the production of reactive oxygen species. CVB-D decreased LPS-induced cytoplasmic iron overload by increasing upregulation of iron uptake molecules. Conversely, CVB-D significantly increased the upregulation of ferroportin 1. CVB-D pretreatment significantly reduced the levels of hamp mRNA compared with the LPS-treated group. CVB-D pretreatment significantly reduced inflammatory factor levels and the ratio of phosphorylated vs. total signal transducer and activator of transcription 3. The expression of SLC7A11 and GPX4 was upregulated in septic cells pretreated with CVB-D, however treatment with ML385 largely decreased this upregulation. Of note, CVB-D inhibited the inward flow of calcium ions through the LTCC. In conclusion, these findings suggest that CVB-D alleviated sepsis-induced cardiac iron toxicity by alleviating iron metabolism.

Hypoadiponectinemia-induced upregulation of microRNA449b downregulating Nrf-1 aggravates cardiac ischemia-reperfusion injury in diabetic mice

Diabetes enhances myocardial ischemic/reperfusion (MI/R) injury via an incompletely understood mechanism. Adiponectin (APN) is a cardioprotective adipokine suppressed by diabetes. However, how hypoadiponectinemia exacerbates cardiac injury remains incompletely understood. Dysregulation of miRNAs plays a significant role in disease development. However, whether hypoadiponectinemia alters cardiac miRNA profile, contributing to diabetic heart injury, remains unclear. Methods and Results: Wild-type (WT) and APN knockout (APN-KO) mice were subjected to MI/R. A cardiac microRNA profile was determined. Among 23 miRNAs increased in APN-KO mice following MI/R, miR-449b was most significantly upregulated (3.98-fold over WT mice). Administrating miR-449b mimic increased apoptosis, enlarged infarct size, and impaired cardiac function in WT mice. In contrast, anti-miR-449b decreased apoptosis, reduced infarct size, and improved cardiac function in APN-KO mice. Bioinformatic analysis predicted 73 miR-449b targeting genes, and GO analysis revealed oxidative stress as the top pathway regulated by these genes. Venn analysis followed by luciferase assay identified Nrf-1 and Ucp3 as the two most important miR-449b targets. In vivo administration of anti-miR-449b in APN-KO mice attenuated MI/R-stimulated superoxide overproduction. In vitro experiments demonstrated that high glucose/high lipid and simulated ischemia/reperfusion upregulated miR-449b and inhibited Nrf-1 and Ucp3 expression. These pathological effects were attenuated by anti-miR-449b or Nrf-1 overexpression. In a final attempt to validate our finding in a clinically relevant model, high-fat diet (HFD)-induced diabetic mice were subjected to MI/R and treated with anti-miR-449b or APN. Diabetes significantly increased miR-449b expression and downregulated Nrf-1 and Ucp3 expression. Administration of anti-miR-449b or APN preserved cardiac Nrf-1 expression, reduced cardiac oxidative stress, decreased apoptosis and infarct size, and improved cardiac function. Conclusion: We demonstrated for the first time that hypoadiponectinemia upregulates miR-449b and suppresses Nrf-1/Ucp3 expression, promoting oxidative stress and exacerbating MI/R injury in this population. Dysregulated APN/miR-449b/oxidative stress pathway is a potential therapeutic target against diabetic MI/R injury.

Strong tissue adhesive polyelectrolyte complex powders based on low molecular weight chitosan for acute hemorrhage control

Self-gelling and bioadhesive powders offered promising effective hemostats to suit irregularly shaped, complex and non-compressible wounds for clinical applications. In the current study, chitosan based polyelectrolyte complex coacervate were simply prepared by mixing high concentrations (10 %) of low molecular weight chitosan (CS) and polyacrylic acid (PAA) solutions. Obtained by lyophilization, the physical cross-linked polyelectrolyte complex powders would form a gel within 5 s upon hydration, which demonstrated excellent mechanical properties, significant antibacterial activities, strong and lasting adhesion on wet tissues in physiological environment. In vitro blood clotting assays showed that the CS/PAA powders could remarkably aggregate blood cells and accelerate blood clotting process. As studied by diverse hemorrhage models, including rat tail, liver and heart injuries and dog incision, CS/PAA powders significantly facilitated the decrease of blood loss as well as hemostatic time by creating robust physical barriers and promoting blood clot formation on the bleeding sites. These outstanding properties in terms of easy preparation, rapid self-gelling, strong wet adhesion, effective hemostasis and shape-adaptability endowed CS/PAA polyelectrolyte complex powders with great potential in managing acute hemorrhage of non-compressible trauma.

Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling

Ischemic cardiac disease is a major cause of mortality worldwide. However, the exact molecular processes underlying this disorder are not fully known. This study includes a comprehensive and coordinated set of invivo and invitro experiments using human cardiac specimens from patients with postischemic heart failure (HF) and healthy control subjects, a murine model of HF, and cellular systems. These approaches identified for the first time a specific pattern of maladaptive chromatin remodeling, namely a double methylation of histone 3 at lysine 27 and a single methylation at lysine 36 (H3_K27me2K36me1) consistently induced by ischemic injury in all these settings: human HF; murine HF; and invitro models. Mechanistically, this work demonstrates that this histone modification mediates the ischemia-induced transcriptional repression of PPARG coactivator 1α (PGC1α), master regulator of mitochondrial function and biogenesis. Intriguingly, both the augmented H3_K27me2K36me1 and the mitochondrial dysfunction ensued by PGC1α down-regulation were significantly attenuated by the treatment with β-hydroxybutyrate, the most abundant ketone body in humans, revealing a novel pathway coupling metabolism to gene expression. Taken together, these findings establish maladaptive chromatin remodeling as a key mechanism in postischemic heart injury, functionally modulated by ketone bodies.

CircHIPK3 exacerbates sepsis-induced acute kidney injury and cardiopulmonary function by regulating microRNA-106a-5p/ROCK2 axis

ObjectiveThis work was implemented to define the regulatory mechanism of the circularHIPK3 (circHIPK3)/microRNA-106a-5p (miR-106a-5p)/rho-associated kinases 2 (ROCK2) axis in sepsis-induced acute kidney injury (AKI) and cardiopulmonary function. MethodsSepsis mouse models were established by cecal ligation and puncture (CLP). circHIPK3, miR-106a-5p and ROCK2 expression levels in kidney, heart and lung tissues were assessed. The cardiac function, lung wet/dry weight ratio, and Evans blue dye leakage were assessed. Serum markers of myocardial injury, serum markers of kidney injury, as well as serum inflammatory cytokines were assessed. The histopathological changes of heart, lung, and kidney tissues were observed. Moreover, correlations of miR-106a-5p, ROCK2, and circHIPK3 were verified. ResultsIn CLP mice after down-regulating circHIPK3 or up-regulating miR-106a-5p, there were increased LVEF and LVFS and decreased LVESD and LVEDD, serum cTnI and CK-MB levels, lung wet/dry weight ratio, Evans blue dye leakage, serum creatinine, BUN and NGAL levels, serum IL-6, TNF and MCP-1 levels, and reduced heart, lung and liver injury in CLP mice. circHIPK3 bound to miR-106a-5p, and miR-106a-5p downregulated ROCK2 expression. miR-106a-5p inhibition or ROCK2 overexpression reversed the delaying effects of circHIPK3 interference. ConclusioncircHIPK3 aggravates sepsis-induced AKI and cardiopulmonary function via sponging miR-106a-5p and promoting ROCK2 expression.

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.

MESNA (2-Mercaptoethanesulfonate) Attenuates Brain, Heart, and Lung Injury Induced by Carotid Ischemia-Reperfusion in Rats.

Ischemia-reperfusion (I/R) causes organ dysfunction as a result of the increased formation of various reactive oxygen metabolites, infiltration of inflammatory cells, interstitial edema, cellular dysfunction, and tissue death. The study aimed to investigate the cytoprotective effect of 2-mercaptoethanesulfonate (MESNA) against tissue damage in rats exposed to carotid ischemia-reperfusion. Twenty-four male Wistar albino rats were divided into four groups (n = 6): sham, carotid I/R, I/R + MESNA (75 mg/kg), and I/R + MESNA (150 mg/kg) groups. To induce ischemia in rats, the carotid arteries were ligated with silk sutures for 10 min; the silk suture was then opened, and 1 h reperfusion was done. MESNA (75 and 150 mg/kg) was administered intraperitoneally 30 min before ischemia-reperfusion. Tissue samples from the animals were taken for histological examination, while the serum levels of some biochemical parameters were utilized to evaluate the systemic alterations. ANOVA and Tukey's post hoc tests were applied with a significance level of 5%. The ischemia-reperfusion-induced tissue damage as evidenced by increase in serum levels of alanine transaminase, aspartate aminotransferase, alkaline phosphatase, malondialdehyde, lactate dehydrogenase, and matrix metalloproteinases (MMP-1, -2, -8) was significantly (P < 0.05-0.0001) reversed after treatment with MESNA in a dose-dependent manner. Treatment with MESNA (75 and 150 mg/kg), significantly (P < 0.05-0.0001) decreased the I/R-induced increase in serum tumor necrosis factor-alpha (TNF-α) and Interleukin-1-beta (IL-1 β). The results of this study suggest that MESNA has a protective effect on tissues by suppressing cellular responses to oxidants and inflammatory mediators associated with carotid ischemia-reperfusion.

Mesenchymal stem cell-derived exosomes: a possible therapeutic strategy for repairing heart injuries.

Mesenchymal stem cells (MSCs) are one of the most potent therapeutic strategies for repairing cardiac injury. It has been shown in the latest studies that MSCs cannot survive in the heart for a long time. Consequently, the exosomes secreted by MSCs may dominate the repair of heart injury and promote the restoration of cardiac cells, vascular proliferation, immune regulation, etc. Based on the current research, the progress of the acting mechanism, application prospects and challenges of exosomes, including non-coding RNA, in repairing cardiac injuries are summarised in this article.

Polarizing Macrophage Functional Phenotype to Foster Cardiac Regeneration.

There is an increasing interest in understanding the connection between the immune and cardiovascular systems, which are highly integrated and communicate through finely regulated cross-talking mechanisms. Recent evidence has demonstrated that the immune system does indeed have a key role in the response to cardiac injury and in cardiac regeneration. Among the immune cells, macrophages appear to have a prominent role in this context, with different subtypes described so far that each have a specific influence on cardiac remodeling and repair. Similarly, there are significant differences in how the innate and adaptive immune systems affect the response to cardiac damage. Understanding all these mechanisms may have relevant clinical implications. Several studies have already demonstrated that stem cell-based therapies support myocardial repair. However, the exact role that cardiac macrophages and their modulation may have in this setting is still unclear. The current need to decipher the dual role of immunity in boosting both heart injury and repair is due, at least for a significant part, to unresolved questions related to the complexity of cardiac macrophage phenotypes. The aim of this review is to provide an overview on the role of the immune system, and of macrophages in particular, in the response to cardiac injury and to outline, through the modulation of the immune response, potential novel therapeutic strategies for cardiac regeneration.

CYP2J deficiency leads to cardiac injury and presents dual regulatory effects on cardiac function in rats

Cytochrome P450 2J2 (CYP2J2) enzyme is widely expressed in aortic endothelial cells and cardiac myocytes and affects cardiac function, but the underlying mechanism is still unclear. Based on CYP2J knockout (KO) rats, we have directly studied the metabolic regulation of CYP2J on cardiac function during aging. The results showed that CYP2J deficiency significantly reduced the content of epoxyeicosatrienoic acids (EETs) in plasma, aggravated myocarditis, myocardial hypertrophy, as well as fibrosis, and inhibited the mitochondrial energy metabolism signal network Pgc-1α/Ampk/Sirt1. With the increase of age, the levels of 11,12-EET and 14,15-EET in plasma of KO rats decreased significantly, and the heart injury was more serious. Interestingly, we found that after CYP2J deletion, the heart initiated a self-protection mechanism by upregulating cardiac mechanism factors Myh7, Dsp, Tnni3, Tnni2, and Scn5a, as well as mitochondrial fusion factors Mfn2 and Opa1. However, this protective effect disappeared with aging. In conclusion, CYP2J deficiency not only reduces the amount of EETs, but also plays a dual regulatory role in cardiac function.