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JCI Insight Apr 2024Myocardial ischemia/reperfusion (MI/R) injury is a major cause of adverse outcomes of revascularization following myocardial infarction. Anaerobic glycolysis during...
Myocardial ischemia/reperfusion (MI/R) injury is a major cause of adverse outcomes of revascularization following myocardial infarction. Anaerobic glycolysis during myocardial ischemia is well studied, but the role of aerobic glycolysis during the early phase of reperfusion is incompletely understood. Lactylation of Histone H3 (H3) is an epigenetic indicator of the glycolytic switch. Heat shock protein A12A (HSPA12A) is an atypic member of the HSP70 family. In the present study, we report that, during reperfusion following myocardial ischemia, HSPA12A was downregulated and aerobic glycolytic flux was decreased in cardiomyocytes. Notably, HSPA12A KO in mice exacerbated MI/R-induced aerobic glycolysis decrease, cardiomyocyte death, and cardiac dysfunction. Gain- and loss-of-function studies demonstrated that HSPA12A was required to support cardiomyocyte survival upon hypoxia/reoxygenation (H/R) challenge and that its protective effects were mediated by maintaining aerobic glycolytic homeostasis for H3 lactylation. Further analyses revealed that HSPA12A increased Smurf1-mediated Hif1α protein stability, thus increasing glycolytic gene expression to maintain appropriate aerobic glycolytic activity to sustain H3 lactylation during reperfusion and, ultimately, improving cardiomyocyte survival to attenuate MI/R injury.
Topics: Animals; Mice; Heat-Shock Proteins; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocytes, Cardiac
PubMed: 38421727
DOI: 10.1172/jci.insight.169125 -
The Journal of Thoracic and... Jun 2021
Topics: Cardiac Surgical Procedures; Heart Ventricles; Heart-Assist Devices; Humans; Myocardial Infarction; Myocardial Reperfusion; Reperfusion Injury; Ventricular Function, Left
PubMed: 32859423
DOI: 10.1016/j.jtcvs.2020.07.078 -
Gaceta Medica de Mexico 2020Mexico has the highest 30-day mortality due to acute myocardial infarction (AMI), which constitutes one of the main causes of mortality in the country: 28 % versus 7.5 %...
INTRODUCTION
Mexico has the highest 30-day mortality due to acute myocardial infarction (AMI), which constitutes one of the main causes of mortality in the country: 28 % versus 7.5 % on average for the Organization for Economic Co-operation and Development member countries.
OBJECTIVE
To establish critical pathways and essential interinstitutional pharmacological strategies for the care of patients with AMI in Mexico, regardless of their socioeconomic status.
METHOD
A group of experts in AMI diagnosis and treatment, representatives of the main public health institutions in Mexico, as well as the Mexican cardiology societies, the Mexican Red Cross and representatives of the Spanish Society of Cardiology, were brought together in order to optimize strategies based on the best existing evidence.
RESULTS
An interinstitutional clinical practice guideline was designed for early diagnosis and timely treatment of AMI with ST-segment elevation, following the clinical horizon of the disease, with the proposal of algorithms that improve the prognosis of patients who attend the emergency services due to an AMI.
CONCLUSION
With these clinical practice guidelines, the group of experts proposes to universalize AMI diagnosis and treatment, regardless of patient socioeconomic status.
INTRODUCCIÓN
México tiene la mortalidad más alta a 30 días por infarto agudo de miocardio (IAM), el cual constituye una de las principales causas de mortalidad en el país: 28 % versus 7.5 % del promedio de los países de la Organización para la Cooperación y el Desarrollo Económicos.
OBJETIVO
Establecer las rutas críticas y las estrategias farmacológicas esenciales interinstitucionales para la atención de los pacientes con IAM en México, independientemente de su condición socioeconómica.
MÉTODO
Se reunió a un grupo de expertos en diagnóstico y tratamiento de IAM, representantes de las principales instituciones públicas de salud de México, así como las sociedades cardiológicas mexicanas, Cruz Roja Mexicana y representantes de la Sociedad Española de Cardiología con la finalidad de optimizar las estrategias con base en la mejor evidencia existente.
RESULTADOS
Se diseñó una guía de práctica clínica interinstitucional para el diagnóstico temprano y tratamiento oportuno del IAM con elevación del segmento ST, siguiendo el horizonte clínico de la enfermedad, con la propuesta de algoritmos que mejoren el pronóstico de los pacientes que acuden por IAM a los servicios de urgencias.
CONCLUSIÓN
Con la presente guía práctica, el grupo de expertos propone universalizar el diagnóstico y tratamiento en el IAM, independientemente de la condición socioeconómica del paciente.
Topics: Biomarkers; COVID-19; Cardiac Rehabilitation; Cause of Death; Consensus; Electrocardiography; Humans; Mexico; Myocardial Reperfusion; Percutaneous Coronary Intervention; ST Elevation Myocardial Infarction; Societies, Medical; Spain; Thrombolytic Therapy
PubMed: 33877123
DOI: 10.24875/GMM.M21000455 -
International Journal of Molecular... Apr 2024Myocardial ischemia/reperfusion injury is reduced by cardioprotective adaptations such as local or remote ischemic conditioning. The cardioprotective stimuli activate... (Review)
Review
Myocardial ischemia/reperfusion injury is reduced by cardioprotective adaptations such as local or remote ischemic conditioning. The cardioprotective stimuli activate signaling cascades, which converge on mitochondria and maintain the function of the organelles, which is critical for cell survival. The signaling cascades include not only extracellular molecules that activate sarcolemmal receptor-dependent or -independent protein kinases that signal at the plasma membrane or in the cytosol, but also involve kinases, which are located to or within mitochondria, phosphorylate mitochondrial target proteins, and thereby modify, e.g., respiration, the generation of reactive oxygen species, calcium handling, mitochondrial dynamics, mitophagy, or apoptosis. In the present review, we give a personal and opinionated overview of selected protein kinases, localized to/within myocardial mitochondria, and summarize the available data on their role in myocardial ischemia/reperfusion injury and protection from it. We highlight the regulation of mitochondrial function by these mitochondrial protein kinases.
Topics: Humans; Signal Transduction; Animals; Myocardial Reperfusion Injury; Mitochondria, Heart; Protein Kinases; Reactive Oxygen Species; Mitochondria
PubMed: 38674076
DOI: 10.3390/ijms25084491 -
Cardiovascular Research Mar 2021Succinate accumulates several-fold in the ischaemic heart and is then rapidly oxidized upon reperfusion, contributing to reactive oxygen species production by...
AIMS
Succinate accumulates several-fold in the ischaemic heart and is then rapidly oxidized upon reperfusion, contributing to reactive oxygen species production by mitochondria. In addition, a significant amount of the accumulated succinate is released from the heart into the circulation at reperfusion, potentially activating the G-protein-coupled succinate receptor (SUCNR1). However, the factors that determine the proportion of succinate oxidation or release, and the mechanism of this release, are not known.
METHODS AND RESULTS
To address these questions, we assessed the fate of accumulated succinate upon reperfusion of anoxic cardiomyocytes, and of the ischaemic heart both ex vivo and in vivo. The release of accumulated succinate was selective and was enhanced by acidification of the intracellular milieu. Furthermore, pharmacological inhibition, or haploinsufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart.
CONCLUSION
Succinate release upon reperfusion of the ischaemic heart is mediated by MCT1 and is facilitated by the acidification of the myocardium during ischaemia. These findings will allow the signalling interaction between succinate released from reperfused ischaemic myocardium and SUCNR1 to be explored.
Topics: Animals; Cells, Cultured; Disease Models, Animal; Female; Isolated Heart Preparation; Male; Metabolome; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Heart; Monocarboxylic Acid Transporters; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocytes, Cardiac; Oxidation-Reduction; Rats; Reactive Oxygen Species; Receptors, G-Protein-Coupled; Succinic Acid; Sus scrofa; Symporters; Time Factors; Mice
PubMed: 32766828
DOI: 10.1093/cvr/cvaa148 -
European Heart Journal Nov 2020
Topics: Blood Pressure; Cardiovascular Diseases; Heart Disease Risk Factors; Heart Failure; Humans; Myocardial Infarction; Myocardial Reperfusion; Risk Factors; Ventricular Dysfunction, Left
PubMed: 33245321
DOI: 10.1093/eurheartj/ehaa834 -
Coronary Artery Disease Sep 2021Despite the progress of cardiovascular medicine, ischemia-reperfusion injury can contribute to increased mortality and prolonged hospitalization after myocardial... (Review)
Review
Despite the progress of cardiovascular medicine, ischemia-reperfusion injury can contribute to increased mortality and prolonged hospitalization after myocardial infarction. Ischemia-reperfusion injury pathophysiology encompasses many cells including cardiomyocytes, fibroblasts, mesenchymal stromal cells, vascular endothelial and smooth muscle cells, platelets, polymorphonuclear cells, macrophages, and T lymphocytes. However, specific mechanisms for all contributing cells and molecular pathways are still under investigation. What is definitely known is that endothelial dysfunction, immunity activation and inflammatory response are crucial events during ischemia-reperfusion injury while toll-like receptors, inflammasomes, reactive oxygen species, intracellular calcium overload and mitochondrial permeability transition pore opening consist of key molecular mediators. Indicatively, cardiac fibroblasts through inflammasome activation mediate the initial inflammatory response. Cardiac mesenchymal stromal cells can respond to myocardial injury by pro-inflammatory activation. Endothelial cell activation contributes to the impaired vasomotion, inflammation and thrombotic events and together with platelet activation leads to microcirculation dysfunction and polymorphonuclear cells recruitment promoting inflammation. Polymorphonuclear cells and monocytes/macrophages subsets are critically involved in the inflammation process by producing toxic proteolytic enzymes and reactive oxygen species. T cells subsets are also involved in several stages of ischemia-reperfusion injury. In this review, we summarize the specific contribution of each of the above cells and the related molecular pathways in the pathophysiology of ischemia-reperfusion injury.
Topics: Blood Platelets; Endothelium, Vascular; Fibroblasts; Humans; Inflammasomes; Macrophages; Mesenchymal Stem Cells; Muscle, Smooth; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Neutrophils; T-Lymphocytes
PubMed: 33471478
DOI: 10.1097/MCA.0000000000000997 -
Med (New York, N.Y.) Jan 2024Ischemic heart disease is the greatest health burden and most frequent cause of death worldwide. Myocardial ischemia/reperfusion is the pathophysiological substrate of... (Review)
Review
Ischemic heart disease is the greatest health burden and most frequent cause of death worldwide. Myocardial ischemia/reperfusion is the pathophysiological substrate of ischemic heart disease. Improvements in prevention and treatment of ischemic heart disease have reduced mortality in developed countries over the last decades, but further progress is now stagnant, and morbidity and mortality from ischemic heart disease in developing countries are increasing. Significant problems remain to be resolved and require a better pathophysiological understanding. The present review attempts to briefly summarize the state of the art in myocardial ischemia/reperfusion research, with a view on both its coronary vascular and myocardial aspects, and to define the cutting edges where further mechanistic knowledge is needed to facilitate translation to clinical practice.
Topics: Humans; Myocardial Reperfusion Injury; Myocardial Ischemia; Myocardial Reperfusion; Myocardium
PubMed: 38218174
DOI: 10.1016/j.medj.2023.12.007 -
Anesthesia and Analgesia Dec 2020Perioperative cardioprotection aims to minimize the consequences of myocardial ischemia-reperfusion injury. In isolated tissue and animal experiments, several treatments... (Review)
Review
Perioperative cardioprotection aims to minimize the consequences of myocardial ischemia-reperfusion injury. In isolated tissue and animal experiments, several treatments have been identified providing cardioprotection. Some of these strategies have been confirmed in clinical proof-of-concept studies. However, the final translation of cardioprotective strategies to really improve clinical outcome has been disappointing: large randomized controlled clinical trials mostly revealed inconclusive, neutral, or negative results. This review provides an overview of the currently available evidence regarding clinical implications of perioperative cardioprotective therapies from an anesthesiological perspective, highlighting nonpharmacological as well as pharmacological strategies. We discuss reasons why translation of promising experimental results into clinical practice and outcome improvement is hampered by potential confounders and suggest future perspectives to overcome these limitations.
Topics: Cardiotonic Agents; Humans; Ischemic Preconditioning, Myocardial; Myocardial Reperfusion Injury; Perioperative Care; Postoperative Complications
PubMed: 33186162
DOI: 10.1213/ANE.0000000000005234 -
Anesthesia and Analgesia Dec 2020Cardioprotection encompasses a variety of strategies protecting the heart against myocardial injury that occurs during and after inadequate blood supply to the heart... (Review)
Review
Cardioprotection encompasses a variety of strategies protecting the heart against myocardial injury that occurs during and after inadequate blood supply to the heart during myocardial infarction. While restoring reperfusion is crucial for salvaging myocardium from further damage, paradoxically, it itself accounts for additional cell death-a phenomenon named ischemia/reperfusion injury. Therefore, therapeutic strategies are necessary to render the heart protected against myocardial infarction. Ischemic pre- and postconditioning, by short periods of sublethal cardiac ischemia and reperfusion, are still the strongest mechanisms to achieve cardioprotection. However, it is highly impractical and far too invasive for clinical use. Fortunately, it can be mimicked pharmacologically, for example, by volatile anesthetics, noble gases, opioids, propofol, dexmedetomidine, and phosphodiesterase inhibitors. These substances are all routinely used in the clinical setting and seem promising candidates for successful translation of cardioprotection from experimental protocols to clinical trials. This review presents the fundamental mechanisms of conditioning strategies and provides an overview of the most recent and relevant findings on different concepts achieving cardioprotection in the experimental setting, specifically emphasizing pharmacological approaches in the perioperative context.
Topics: Analgesics, Opioid; Cardiotonic Agents; Humans; Ischemic Preconditioning, Myocardial; Myocardial Reperfusion Injury; Perioperative Care; Phosphodiesterase 3 Inhibitors; Postoperative Complications
PubMed: 33186163
DOI: 10.1213/ANE.0000000000005243