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Frontiers in Pharmacology 2024Ischemic heart disease, associated with high morbidity and mortality, represents a major challenge for the development of drug-based strategies to improve its prognosis.... (Review)
Review
Re-evaluation of the cardioprotective effects of cannabinoids against ischemia-reperfusion injury according to the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria.
Ischemic heart disease, associated with high morbidity and mortality, represents a major challenge for the development of drug-based strategies to improve its prognosis. Results of pre-clinical studies suggest that agonists of cannabinoid CB receptors and multitarget cannabidiol might be potential cardioprotective strategies against ischemia-reperfusion injury. The aim of our study was to re-evaluate the cardioprotective effects of cannabinoids against ischemia-reperfusion injury according to the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria published recently by the European Union (EU) CARDIOPROTECTION COST ACTION. To meet the minimum criteria of those guidelines, experiments should be performed (i) on healthy small animals subjected to ischemia with reperfusion lasting for at least 2 hours and (ii) confirmed in small animals with comorbidities and co-medications and (iii) in large animals. Our analysis revealed that the publications regarding cardioprotective effects of CB receptor agonists and cannabidiol did not meet all three strict steps of IMPACT. Thus, additional experiments are needed to confirm the cardioprotective activities of (endo)cannabinoids mainly on small animals with comorbidities and on large animals. Moreover, our publication underlines the significance of the IMPACT criteria for a proper planning of preclinical experiments regarding cardiac ischemia-reperfusion injury.
PubMed: 38873412
DOI: 10.3389/fphar.2024.1382995 -
Biomedicine & Pharmacotherapy =... Jul 2024Echinops plants have received great attention for the treatment of many diseases due to pharmacological properties such as their antidiabetic, antioxidant, and...
Cardioprotective effects of the aqueous extract of Echinops cephalotes on myocardial ischemia-reperfusion in rats by modulation of MMP-2, MMP-9, TIMP, and oxidative stress.
Echinops plants have received great attention for the treatment of many diseases due to pharmacological properties such as their antidiabetic, antioxidant, and anti-inflammatory characteristics. The major purpose of the present study was to investigate the cardioprotective benefits of Echinops cephalotes (Ech) against myocardial ischemia-reperfusion (MI/R) injury. Male Wistar rats were randomly allocated to three groups: sham, MI, and MI + Ech. The left coronary artery (LAD) was blocked for 30 minutes to induce MI. In the treatment group, rats were given 150 mg/kg/day of Ech extract for 28 days. Aqueous extracts were made from Echinops plants. To study heart function, fibrosis, cardiac damage indicators, and oxidative stress factors, echocardiography, Masson's trichrome staining, and biochemical tests were used. The expression of matrix metalloproteinase 2 and 9 (MMP2 and MMP-9) and tissue inhibitor of metalloproteinase (TIMP) was determined using Western blotting. Tissue damage was assessed using hematoxylin and eosin staining. MI group exhibited significantly reduced ejection fraction (EF) and fractional shortening (FS), enhanced levels of lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), cardiac Troponin I (cTnI), and malondialdehyde (MDA), as well as a decrease in the Glutathione (GSH) tissue content, reduced activity of superoxide dismutase (SOD), increasing fibrosis, upregulations of MMP-2 and MMP-9, and reduction of TIMP compared to the sham group. The findings suggest that Ech in particular, could be a promising therapeutic agent to reduce the damage in MI by targeting oxidative stress and modulating the activities of matrix metalloproteinases and their tissue inhibitors.
Topics: Animals; Male; Oxidative Stress; Rats, Wistar; Matrix Metalloproteinase 2; Plant Extracts; Matrix Metalloproteinase 9; Myocardial Reperfusion Injury; Cardiotonic Agents; Rats; Myocardium; Tissue Inhibitor of Metalloproteinases; Fibrosis; Water; Antioxidants
PubMed: 38870633
DOI: 10.1016/j.biopha.2024.116927 -
Cureus May 2024Left ventricular thrombus is a major complication following myocardial infarction, particularly in patients with anterior myocardial infarction or dilated...
Left ventricular thrombus is a major complication following myocardial infarction, particularly in patients with anterior myocardial infarction or dilated cardiomyopathies regardless of coronary reperfusion therapy. Embolization of mural thrombus is one of the major causes of large vessel occlusion ischemic stroke. A combination therapy of antiplatelet (single or dual antiplatelet) and anticoagulant is mandatory in the management of myocardial infarction and left ventricular thrombus with or without stroke. To our knowledge, there are no guidelines on the optimal regimen (dual or triple therapies) and timing of administration in cases of cardio-cerebral infarction. It is difficult for clinicians to balance the risks of intracranial hemorrhage and coronary stent thrombosis. Here, we describe the case of a gentleman who had recently undergone coronary intervention and presented with ischemic stroke and left ventricular thrombus, along with the management challenges in this scenario.
PubMed: 38868266
DOI: 10.7759/cureus.60196 -
Cardiovascular Diabetology Jun 2024The specific pathophysiological pathways through which diabetes exacerbates myocardial ischemia/reperfusion (I/R) injury remain unclear; however, dysregulation of immune...
Y4 RNA fragments from cardiosphere-derived cells ameliorate diabetic myocardial ischemia‒reperfusion injury by inhibiting protein kinase C β-mediated macrophage polarization.
The specific pathophysiological pathways through which diabetes exacerbates myocardial ischemia/reperfusion (I/R) injury remain unclear; however, dysregulation of immune and inflammatory cells, potentially driven by abnormalities in their number and function due to diabetes, may play a significant role. In the present investigation, we simulated myocardial I/R injury by inducing ischemia through ligation of the left anterior descending coronary artery in mice for 40 min, followed by reperfusion for 24 h. Previous studies have indicated that protein kinase Cβ (PKCβ) is upregulated under hyperglycemic conditions and is implicated in the development of various diabetic complications. The Y4 RNA fragment is identified as the predominant small RNA component present in the extracellular vesicles of cardio sphere-derived cells (CDCs), exhibiting notable anti-inflammatory properties in the contexts of myocardial infarction and cardiac hypertrophy. Our investigation revealed that the administration of Y4 RNA into the ventricular cavity of db/db mice following myocardial I/R injury markedly enhanced cardiac function. Furthermore, Y4 RNA was observed to facilitate M2 macrophage polarization and interleukin-10 secretion through the suppression of PKCβ activation. The mechanism by which Y4 RNA affects PKCβ by regulating macrophage activation within the inflammatory environment involves the inhibition of ERK1/2 phosphorylation In our study, the role of PKCβ in regulating macrophage polarization during myocardial I/R injury was investigated through the use of PKCβ knockout mice. Our findings indicate that PKCβ plays a crucial role in modulating the inflammatory response associated with macrophage activation in db/db mice experiencing myocardial I/R, with a notable exacerbation of this response observed upon significant upregulation of PKCβ expression. In vitro studies further elucidated the protective mechanism by which Y4 RNA modulates the PKCβ/ERK1/2 signaling pathway to induce M2 macrophage activation. Overall, our findings suggest that Y4 RNA plays an anti-inflammatory role in diabetic I/R injury, suggesting a novel therapeutic approach for managing myocardial I/R injury in diabetic individuals.
Topics: Animals; Protein Kinase C beta; Myocardial Reperfusion Injury; Macrophages; Disease Models, Animal; Male; Mice, Inbred C57BL; Signal Transduction; Interleukin-10; Mice; Diabetic Cardiomyopathies; Cells, Cultured; Phenotype; Myocytes, Cardiac; Mitogen-Activated Protein Kinase 3; Macrophage Activation; Mitogen-Activated Protein Kinase 1; Ventricular Function, Left; Phosphorylation
PubMed: 38867293
DOI: 10.1186/s12933-024-02247-6 -
Molecular Medicine (Cambridge, Mass.) Jun 2024Programmed cell death is an important mechanism for the development of hepatic ischemia and reperfusion (IR) injury, and multiple novel forms of programmed cell death...
BACKGROUND
Programmed cell death is an important mechanism for the development of hepatic ischemia and reperfusion (IR) injury, and multiple novel forms of programmed cell death are involved in the pathological process of hepatic IR. ERRFI1 is involved in the regulation of cell apoptosis in myocardial IR. However, the function of ERRFI1 in hepatic IR injury and its modulation of programmed cell death remain largely unknown.
METHODS
Here, we performed functional and molecular mechanism studies in hepatocyte-specific knockout mice and ERRFI1-silenced hepatocytes to investigate the significance of ERRFI1 in hepatic IR injury. The histological severity of livers, enzyme activities, hepatocyte apoptosis and ferroptosis were determined.
RESULTS
ERRFI1 expression increased in liver tissues from mice with IR injury and hepatocytes under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Hepatocyte-specific ERRFI1 knockout alleviated IR-induced liver injury in mice by reducing cell apoptosis and ferroptosis. ERRFI1 knockdown reduced apoptotic and ferroptotic hepatocytes induced by OGD/R. Mechanistically, ERRFI1 interacted with GRB2 to maintain its stability by hindering its proteasomal degradation. Overexpression of GRB2 abrogated the effects of ERRFI1 silencing on hepatocyte apoptosis and ferroptosis.
CONCLUSIONS
Our results revealed that the ERRFI1-GRB2 interaction and GRB2 stability are essential for ERRFI1-regulated hepatic IR injury, indicating that inhibition of ERRFI1 or blockade of the ERRFI1-GRB2 interaction may be potential therapeutic strategies in response to hepatic IR injury.
Topics: Animals; Humans; Male; Mice; Apoptosis; Disease Models, Animal; Ferroptosis; GRB2 Adaptor Protein; Hepatocytes; Liver; Mice, Knockout; Reperfusion Injury
PubMed: 38862918
DOI: 10.1186/s10020-024-00837-4 -
Theranostics 2024Myocardial infarction (MI) as a consequence of atherosclerosis-associated acute thrombosis is a leading cause of death and disability globally. Antiplatelet and...
Platelet-targeted thromboprophylaxis with a human serum albumin fusion drug: Preventing thrombosis and reducing cardiac ischemia/reperfusion injurywithout bleeding complications.
Myocardial infarction (MI) as a consequence of atherosclerosis-associated acute thrombosis is a leading cause of death and disability globally. Antiplatelet and anticoagulant drugs are standard therapies in preventing and treating MI. However, all clinically used drugs are associated with bleeding complications, which ultimately limits their use in patients with a high risk of bleeding. We have developed a new recombinant drug, targ-HSA-TAP, that combines targeting and specific inhibition of activated platelets as well as anticoagulation. This drug is designed and tested for a prolonged circulating half-life, enabling unique thromboprophylaxis without bleeding complications. Targ-HSA-TAP combines a single-chain antibody (scFv) that targets activated glycoprotein IIb/IIIa on activated platelets, human serum albumin (HSA) for prolonged circulation, and tick anticoagulant peptide (TAP) for coagulation FX inhibition. A non-binding scFv is employed as a non-targeting control (non-targ-HSA-TAP). Its efficacy was investigated using murine models of acute thrombosis and cardiac ischemia-reperfusion (I/R) injury. Our experiments confirmed the targeting specificity of targ-HSA-TAP to activated platelets and demonstrated effective prevention of platelet aggregation and thrombus formation, as well as FXa inhibition . Thromboprophylactic administration of targ-HSA-TAP subcutaneously in mice prevented occlusion of the carotid artery after ferric chloride injury as compared to non-targ-HSA-TAP and PBS-control treated mice. By comparing the therapeutic outcomes between targ-TAP and targ-HSA-TAP, we demonstrate the significant improvements brought by the HSA fusion in extending the drug's half-life and enhancing its therapeutic window for up to 16 h post-administration. Importantly, tail bleeding time was not prolonged with targ-HSA-TAP in contrast to the clinically used anticoagulant enoxaparin. Furthermore, in a murine model of cardiac I/R injury, mice administered targ-HSA-TAP 10 h before injury demonstrated preserved cardiac function, with significantly higher ejection fraction and fractional shortening, as compared to the non-targ-HSA-TAP and PBS control groups. Advanced strain analysis revealed reduced myocardial deformation and histology confirmed a reduced infarct size in targ-HSA-TAP treated mice compared to control groups. The inclusion of HSA represents a significant advancement in the design of targeted therapeutic agents for thromboprophylaxis. Our activated platelet-targeted targ-HSA-TAP is a highly effective antithrombotic drug with both anticoagulant and antiplatelet effects while retaining normal hemostasis. The long half-life of targ-HSA-TAP provides the unique opportunity to use this antithrombotic drug for more effective, long-lasting and safer anti-thrombotic prophylaxis. In cases where MI occurs, this prophylactic strategy reduces thrombus burden and effectively reduces cardiac I/R injury.
Topics: Animals; Serum Albumin, Human; Mice; Thrombosis; Humans; Hemorrhage; Blood Platelets; Disease Models, Animal; Male; Anticoagulants; Single-Chain Antibodies; Myocardial Reperfusion Injury; Myocardial Infarction; Mice, Inbred C57BL; Recombinant Fusion Proteins
PubMed: 38855181
DOI: 10.7150/thno.97517 -
Cureus May 2024This case report delineates the clinical trajectory and management strategies of a 59-year-old Hispanic male diagnosed with a left ventricular pseudoaneurysm (LVPA)...
This case report delineates the clinical trajectory and management strategies of a 59-year-old Hispanic male diagnosed with a left ventricular pseudoaneurysm (LVPA) following a delayed presentation of ST-segment elevation myocardial infarction (STEMI), for which reperfusion treatment was not administered. Initially, an echocardiogram demonstrated an extensive anterolateral myocardial infarction, severe left ventricular systolic dysfunction, and an early-stage left ventricular apical aneurysm with thrombus, leading to the initiation of warfarin. Metabolic myocardial perfusion imaging via positron emission tomography indicated a substantial myocardial scar without viability, guiding the decision against revascularization. Post discharge, the patient, equipped with a wearable cardioverter defibrillator for sudden cardiac death prevention, experienced symptomatic ventricular tachycardia, which was resolved with defibrillator shocks. Subsequent imaging revealed an acute LVPA adjacent to the existing left ventricular aneurysm. Given the high surgical risk, conservative management was elected, resulting in thrombosis and closure of the pseudoaneurysm after two weeks. The patient eventually transitioned to home hospice, surviving an additional five months. This report underscores the complexities and therapeutic dilemmas in managing post-MI LVPA patients who are ineligible for surgical intervention.
PubMed: 38854241
DOI: 10.7759/cureus.60026 -
BioRxiv : the Preprint Server For... Jun 2024We and others discovered a highly-conserved mitochondrial transmembrane microprotein, named Mitoregulin (Mtln), that supports lipid metabolism. We reported that Mtln...
We and others discovered a highly-conserved mitochondrial transmembrane microprotein, named Mitoregulin (Mtln), that supports lipid metabolism. We reported that Mtln strongly binds cardiolipin (CL), increases mitochondrial respiration and Ca retention capacities, and reduces reactive oxygen species (ROS). Here we extend our observation of Mtln-CL binding and examine Mtln influence on cristae structure and mitochondrial membrane integrity during stress. We demonstrate that mitochondria from constitutive- and inducible Mtln-knockout (KO) mice are susceptible to membrane freeze-damage and that this can be rescued by acute Mtln re-expression. In mitochondrial-simulated lipid monolayers, we show that synthetic Mtln decreases lipid packing and monolayer elasticity. Lipidomics revealed that Mtln-KO heart tissues show broad decreases in 22:6-containing lipids and increased cardiolipin damage/remodeling. Lastly, we demonstrate that Mtln-KO mice suffer worse myocardial ischemia-reperfusion injury, hinting at a translationally-relevant role for Mtln in cardioprotection. Our work supports a model in which Mtln binds cardiolipin and stabilizes mitochondrial membranes to broadly influence diverse mitochondrial functions, including lipid metabolism, while also protecting against stress.
PubMed: 38853979
DOI: 10.1101/2024.05.31.596875 -
Biomedicine & Pharmacotherapy =... Jul 2024Integrated stress response (ISR) is activated to promote cell survival by maintaining the phosphorylation of eukaryotic translation initiation factor 2 (eIF2α). We...
OBJECTIVE
Integrated stress response (ISR) is activated to promote cell survival by maintaining the phosphorylation of eukaryotic translation initiation factor 2 (eIF2α). We investigated whether Sephin1 enhances ISR and attenuates myocardial ischemia-reperfusion (MIR) injury.
METHODS
Male C57BL/6 J mice were injected with Sephin1 (2 mg/kg,i.p.) 30 min before surgery to establish a model of MIR with 45 min ischemia and 180 min reperfusion. In vitro, the H9C2 cell line with hypoxia-reoxygenation (H/R) was used to simulate MIR. Myocardial injury was evaluated by echocardiography, histologic observation after staining with TTC and H&E and electron microscopy. ISR, autophagy and apoptosis in vivo and in vitro were evaluated by immunoblotting, immunohistochemistry, immunofluorescence, and flow cytometry, respectively. Global protein synthesis was determined using a non-radioactive SUnSET Assay based on the puromycin method. Autophinib, an autophagy-specific inhibitor, was used to investigate the correlation between autophagy and apoptosis in the presence of Sephin1.
RESULTS
In vivo, Sephin1 significantly reduced myocardial injury and improved the cardiac function in MIR mice. Sephin1 administration prolonged ISR, reduced cell apoptosis, and promoted autophagy. In vitro, Sephin1 increased the number of stress granules (SGs) and autophagic vesicles, enhanced ISR and related protein synthesis suppression, and reduced cell apoptosis. Autophinib partly reversed autophagosome formation and apoptosis in H9c2 cells.
CONCLUSIONS
Sephin1 enhances ISR and related protein synthesis suppression, ameliorates myocardial apoptosis, and promotes autophagy during MIR stress. Sephin1 could act as a noval ISR enhancer for managing acute myocardial ischemia disease.
Topics: Animals; Autophagy; Male; Myocardial Reperfusion Injury; Mice, Inbred C57BL; Mice; Apoptosis; Cell Line; Myocytes, Cardiac; Disease Models, Animal; Erythropoietin; Peptide Fragments
PubMed: 38850665
DOI: 10.1016/j.biopha.2024.116869 -
Scientific Reports Jun 2024Extracorporeal cardiopulmonary resuscitation (ECPR) is emerging as a feasible and effective rescue strategy for prolonged cardiac arrest (CA). However, prolonged total...
Extracorporeal cardiopulmonary resuscitation (ECPR) is emerging as a feasible and effective rescue strategy for prolonged cardiac arrest (CA). However, prolonged total body ischemia and reperfusion can cause microvascular occlusion that prevents organ reperfusion and recovery of function. One hypothesized mechanism of microvascular "no-reflow" is leukocyte adhesion and formation of neutrophil extracellular traps. In this study we tested the hypothesis that a leukocyte filter (LF) or leukocyte modulation device (L-MOD) could reduce NETosis and improve recovery of heart and brain function in a swine model of prolonged cardiac arrest treated with ECPR. Thirty-six swine (45.5 ± 2.5 kg, evenly distributed sex) underwent 8 min of untreated ventricular fibrillation CA followed by 30 min of mechanical CPR with subsequent 8 h of ECPR. Two females were later excluded from analysis due to CPR complications. Swine were randomized to standard care (Control group), LF, or L-MOD at the onset of CPR. NET formation was quantified by serum dsDNA and citrullinated histone as well as immunofluorescence staining of the heart and brain for citrullinated histone in the microvasculature. Primary outcomes included recovery of cardiac function based on cardiac resuscitability score (CRS) and recovery of neurologic function based on the somatosensory evoked potential (SSEP) N20 cortical response. In this model of prolonged CA treated with ECPR we observed significant increases in serum biomarkers of NETosis and immunohistochemical evidence of microvascular NET formation in the heart and brain that were not reduced by LF or L-MOD therapy. Correspondingly, there were no significant differences in CRS and SSEP recovery between Control, LF, and L-MOD groups 8 h after ECPR onset (CRS = 3.1 ± 2.7, 3.7 ± 2.6, and 2.6 ± 2.6 respectively; p = 0.606; and SSEP = 27.9 ± 13.0%, 36.7 ± 10.5%, and 31.2 ± 9.8% respectively, p = 0.194). In this model of prolonged CA treated with ECPR, the use of LF or L-MOD therapy during ECPR did not reduce microvascular NETosis or improve recovery of myocardial or brain function. The causal relationship between microvascular NETosis, no-reflow, and recovery of organ function after prolonged cardiac arrest treated with ECPR requires further investigation.
Topics: Animals; Heart Arrest; Cardiopulmonary Resuscitation; Swine; Female; Disease Models, Animal; Male; Extracorporeal Membrane Oxygenation; Leukocytes; Extracellular Traps; Leukocyte Reduction Procedures
PubMed: 38844477
DOI: 10.1038/s41598-024-63522-w