Myocardial Reperfusion Injury: Damage to the MYOCARDIUM resulting from MYOCARDIAL REPERFUSION (restoration of blood flow to ischemic areas of the HEART.) Reperfusion takes place when there is spontaneous thrombolysis, THROMBOLYTIC THERAPY, collateral flow from other coronary vascular beds, or reversal of vasospasm.Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing MYOCARDIAL REPERFUSION INJURY.Reperfusion Injury: Adverse functional, metabolic, or structural changes in ischemic tissues resulting from the restoration of blood flow to the tissue (REPERFUSION), including swelling; HEMORRHAGE; NECROSIS; and damage from FREE RADICALS. The most common instance is MYOCARDIAL REPERFUSION INJURY.Ischemic Postconditioning: The application of repeated, brief periods of vascular occlusion at the onset of REPERFUSION to reduce REPERFUSION INJURY that follows a prolonged ischemic event. The techniques are similar to ISCHEMIC PRECONDITIONING but the time of application is after the ischemic event instead of before.Myocardial Infarction: NECROSIS of the MYOCARDIUM caused by an obstruction of the blood supply to the heart (CORONARY CIRCULATION).Myocardium: The muscle tissue of the HEART. It is composed of striated, involuntary muscle cells (MYOCYTES, CARDIAC) connected to form the contractile pump to generate blood flow.Creatine Kinase: A transferase that catalyzes formation of PHOSPHOCREATINE from ATP + CREATINE. The reaction stores ATP energy as phosphocreatine. Three cytoplasmic ISOENZYMES have been identified in human tissues: the MM type from SKELETAL MUSCLE, the MB type from myocardial tissue and the BB type from nervous tissue as well as a mitochondrial isoenzyme. Macro-creatine kinase refers to creatine kinase complexed with other serum proteins.Cardioplegic Solutions: Solutions which, upon administration, will temporarily arrest cardiac activity. They are used in the performance of heart surgery.Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (CORONARY ARTERY DISEASE), to obstruction by a thrombus (CORONARY THROMBOSIS), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (MYOCARDIAL INFARCTION).Coronary Circulation: The circulation of blood through the CORONARY VESSELS of the HEART.Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC Agents: Agents that have a strengthening effect on the heart or that can increase cardiac output. They may be CARDIAC GLYCOSIDES; SYMPATHOMIMETICS; or other drugs. They are used after MYOCARDIAL INFARCT; CARDIAC SURGICAL PROCEDURES; in SHOCK; or in congestive heart failure (HEART FAILURE).Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing REPERFUSION INJURY.P-Selectin: Cell adhesion molecule and CD antigen that mediates the adhesion of neutrophils and monocytes to activated platelets and endothelial cells.Disease Models, Animal: Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.Hemodynamics: The movement and the forces involved in the movement of the blood through the CARDIOVASCULAR SYSTEM.Heart: The hollow, muscular organ that maintains the circulation of the blood.Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects.Rats, Wistar: A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain.Rats, Sprague-Dawley: A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.Dogs: The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065)Myocardial Contraction: Contractile activity of the MYOCARDIUM.Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.Thrombectomy: Surgical removal of an obstructing clot or foreign material from a blood vessel at the point of its formation. Removal of a clot arising from a distant site is called EMBOLECTOMY.Wounds and Injuries: Damage inflicted on the body as the direct or indirect result of an external force, with or without disruption of structural continuity.Ischemic Preconditioning, Myocardial: Exposure of myocardial tissue to brief, repeated periods of vascular occlusion in order to render the myocardium resistant to the deleterious effects of ISCHEMIA or REPERFUSION. The period of pre-exposure and the number of times the tissue is exposed to ischemia and reperfusion vary, the average being 3 to 5 minutes.Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Angioplasty, Balloon, Coronary: Dilation of an occluded coronary artery (or arteries) by means of a balloon catheter to restore myocardial blood supply.Electrocardiography: Recording of the moment-to-moment electromotive forces of the HEART as projected onto various sites on the body's surface, delineated as a scalar function of time. The recording is monitored by a tracing on slow moving chart paper or by observing it on a cardioscope, which is a CATHODE RAY TUBE DISPLAY.Brain Injuries: Acute and chronic (see also BRAIN INJURIES, CHRONIC) injuries to the brain, including the cerebral hemispheres, CEREBELLUM, and BRAIN STEM. Clinical manifestations depend on the nature of injury. Diffuse trauma to the brain is frequently associated with DIFFUSE AXONAL INJURY or COMA, POST-TRAUMATIC. Localized injuries may be associated with NEUROBEHAVIORAL MANIFESTATIONS; HEMIPARESIS, or other focal neurologic deficits.Ischemic Preconditioning: A technique in which tissue is rendered resistant to the deleterious effects of prolonged ISCHEMIA and REPERFUSION by prior exposure to brief, repeated periods of vascular occlusion. (Am J Physiol 1995 May;268(5 Pt 2):H2063-7, Abstract)Ventricular Function, Left: The hemodynamic and electrophysiological action of the left HEART VENTRICLE. Its measurement is an important aspect of the clinical evaluation of patients with heart disease to determine the effects of the disease on cardiac performance.Perfusion: Treatment process involving the injection of fluid into an organ or tissue.Heart Arrest, Induced: A procedure to stop the contraction of MYOCARDIUM during HEART SURGERY. It is usually achieved with the use of chemicals (CARDIOPLEGIC SOLUTIONS) or cold temperature (such as chilled perfusate).Thrombolytic Therapy: Use of infusions of FIBRINOLYTIC AGENTS to destroy or dissolve thrombi in blood vessels or bypass grafts.Coronary Vessels: The veins and arteries of the HEART.Coronary Angiography: Radiography of the vascular system of the heart muscle after injection of a contrast medium.Necrosis: The pathological process occurring in cells that are dying from irreparable injuries. It is caused by the progressive, uncontrolled action of degradative ENZYMES, leading to MITOCHONDRIAL SWELLING, nuclear flocculation, and cell lysis. It is distinct it from APOPTOSIS, which is a normal, regulated cellular process.Ischemia: A hypoperfusion of the BLOOD through an organ or tissue caused by a PATHOLOGIC CONSTRICTION or obstruction of its BLOOD VESSELS, or an absence of BLOOD CIRCULATION.Creatine Kinase, MB Form: An isoenzyme of creatine kinase found in the CARDIAC MUSCLE.Mitochondria, Heart: The mitochondria of the myocardium.Myocytes, Cardiac: Striated muscle cells found in the heart. They are derived from cardiac myoblasts (MYOBLASTS, CARDIAC).Anterior Wall Myocardial Infarction: MYOCARDIAL INFARCTION in which the anterior wall of the heart is involved. Anterior wall myocardial infarction is often caused by occlusion of the left anterior descending coronary artery. It can be categorized as anteroseptal or anterolateral wall myocardial infarction.Coronary Thrombosis: Coagulation of blood in any of the CORONARY VESSELS. The presence of a blood clot (THROMBUS) often leads to MYOCARDIAL INFARCTION.Mitochondrial Membrane Transport Proteins: Proteins involved in the transport of specific substances across the membranes of the MITOCHONDRIA.Percutaneous Coronary Intervention: A family of percutaneous techniques that are used to manage CORONARY OCCLUSION, including standard balloon angioplasty (PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY), the placement of intracoronary STENTS, and atheroablative technologies (e.g., ATHERECTOMY; ENDARTERECTOMY; THROMBECTOMY; PERCUTANEOUS TRANSLUMINAL LASER ANGIOPLASTY). PTCA was the dominant form of PCI, before the widespread use of stenting.Athletic Injuries: Injuries incurred during participation in competitive or non-competitive sports.Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, and practicability of these interventions in individual cases or series.Microcirculation: The circulation of the BLOOD through the MICROVASCULAR NETWORK.Spinal Cord Injuries: Penetrating and non-penetrating injuries to the spinal cord resulting from traumatic external forces (e.g., WOUNDS, GUNSHOT; WHIPLASH INJURIES; etc.).Malondialdehyde: The dialdehyde of malonic acid.Acute Kidney Injury: Abrupt reduction in kidney function. Acute kidney injury encompasses the entire spectrum of the syndrome including acute kidney failure; ACUTE KIDNEY TUBULAR NECROSIS; and other less severe conditions.Warm Ischemia: A tissue or organ remaining at physiological temperature during decreased BLOOD perfusion or in the absence of blood supply. During ORGAN TRANSPLANTATION it begins when the organ reaches physiological temperature before the completion of SURGICAL ANASTOMOSIS and ends with reestablishment of the BLOOD CIRCULATION through the tissue.Lung Injury: Damage to any compartment of the lung caused by physical, chemical, or biological agents which characteristically elicit inflammatory reaction. These inflammatory reactions can either be acute and dominated by NEUTROPHILS, or chronic and dominated by LYMPHOCYTES and MACROPHAGES.Protective Agents: Synthetic or natural substances which are given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent.Mice, Inbred C57BLRabbits: The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.Immunoglobulin Fab Fragments: Univalent antigen-binding fragments composed of one entire IMMUNOGLOBULIN LIGHT CHAIN and the amino terminal end of one of the IMMUNOGLOBULIN HEAVY CHAINS from the hinge region, linked to each other by disulfide bonds. Fab contains the IMMUNOGLOBULIN VARIABLE REGIONS, which are part of the antigen-binding site, and the first IMMUNOGLOBULIN CONSTANT REGIONS. This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme PAPAIN.Platelet Glycoprotein GPIIb-IIIa Complex: Platelet membrane glycoprotein complex important for platelet adhesion and aggregation. It is an integrin complex containing INTEGRIN ALPHAIIB and INTEGRIN BETA3 which recognizes the arginine-glycine-aspartic acid (RGD) sequence present on several adhesive proteins. As such, it is a receptor for FIBRINOGEN; VON WILLEBRAND FACTOR; FIBRONECTIN; VITRONECTIN; and THROMBOSPONDINS. A deficiency of GPIIb-IIIa results in GLANZMANN THROMBASTHENIA.Swine: Any of various animals that constitute the family Suidae and comprise stout-bodied, short-legged omnivorous mammals with thick skin, usually covered with coarse bristles, a rather long mobile snout, and small tail. Included are the genera Babyrousa, Phacochoerus (wart hogs), and Sus, the latter containing the domestic pig (see SUS SCROFA).Echocardiography: Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic.Brain Ischemia: Localized reduction of blood flow to brain tissue due to arterial obstruction or systemic hypoperfusion. This frequently occurs in conjunction with brain hypoxia (HYPOXIA, BRAIN). Prolonged ischemia is associated with BRAIN INFARCTION.Apoptosis: One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components.Injury Severity Score: An anatomic severity scale based on the Abbreviated Injury Scale (AIS) and developed specifically to score multiple traumatic injuries. It has been used as a predictor of mortality.Neutrophil Infiltration: The diffusion or accumulation of neutrophils in tissues or cells in response to a wide variety of substances released at the sites of inflammatory reactions.Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi).L-Lactate Dehydrogenase: A tetrameric enzyme that, along with the coenzyme NAD+, catalyzes the interconversion of LACTATE and PYRUVATE. In vertebrates, genes for three different subunits (LDH-A, LDH-B and LDH-C) exist.Liver: A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.Leg Injuries: General or unspecified injuries involving the leg.Cold Ischemia: The chilling of a tissue or organ during decreased BLOOD perfusion or in the absence of blood supply. Cold ischemia time during ORGAN TRANSPLANTATION begins when the organ is cooled with a cold perfusion solution after ORGAN PROCUREMENT surgery, and ends after the tissue reaches physiological temperature during implantation procedures.Organ Preservation: The process by which organs are kept viable outside of the organism from which they were removed (i.e., kept from decay by means of a chemical agent, cooling, or a fluid substitute that mimics the natural state within the organism).Kidney: Body organ that filters blood for the secretion of URINE and that regulates ion concentrations.Cytoprotection: The process by which chemical compounds provide protection to cells against harmful agents.Organ Preservation Solutions: Solutions used to store organs and minimize tissue damage, particularly while awaiting implantation.Acute Lung Injury: A condition of lung damage that is characterized by bilateral pulmonary infiltrates (PULMONARY EDEMA) rich in NEUTROPHILS, and in the absence of clinical HEART FAILURE. This can represent a spectrum of pulmonary lesions, endothelial and epithelial, due to numerous factors (physical, chemical, or biological).Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC Transaminase: An enzyme that catalyzes the conversion of L-alanine and 2-oxoglutarate to pyruvate and L-glutamate. (From Enzyme Nomenclature, 1992) EC Aminotransferases: Enzymes of the transferase class that catalyze the conversion of L-aspartate and 2-ketoglutarate to oxaloacetate and L-glutamate. EC, Knockout: Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group.Eye Injuries: Damage or trauma inflicted to the eye by external means. The concept includes both surface injuries and intraocular injuries.Models, Animal: Non-human animals, selected because of specific characteristics, for use in experimental research, teaching, or testing.Coronary Disease: An imbalance between myocardial functional requirements and the capacity of the CORONARY VESSELS to supply sufficient blood flow. It is a form of MYOCARDIAL ISCHEMIA (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels.Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated.Infarction, Middle Cerebral Artery: NECROSIS occurring in the MIDDLE CEREBRAL ARTERY distribution system which brings blood to the entire lateral aspects of each CEREBRAL HEMISPHERE. Clinical signs include impaired cognition; APHASIA; AGRAPHIA; weak and numbness in the face and arms, contralaterally or bilaterally depending on the infarction.Antioxidants: Naturally occurring or synthetic substances that inhibit or retard the oxidation of a substance to which it is added. They counteract the harmful and damaging effects of oxidation in animal tissues.Neck Injuries: General or unspecified injuries to the neck. It includes injuries to the skin, muscles, and other soft tissues of the neck.Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells, synthesized from ARGININE by NITRIC OXIDE SYNTHASE. Nitric oxide is one of the ENDOTHELIUM-DEPENDENT RELAXING FACTORS released by the vascular endothelium and mediates VASODILATION. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic GUANYLATE CYCLASE and thus elevates intracellular levels of CYCLIC GMP.Free Radical Scavengers: Substances that influence the course of a chemical reaction by ready combination with free radicals. Among other effects, this combining activity protects pancreatic islets against damage by cytokines and prevents myocardial and pulmonary perfusion injuries.Myocardial Stunning: Prolonged dysfunction of the myocardium after a brief episode of severe ischemia, with gradual return of contractile activity.Neuroprotective Agents: Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids.Constriction: The act of constricting.Stents: Devices that provide support for tubular structures that are being anastomosed or for body cavities during skin grafting.Predictive Value of Tests: In screening and diagnostic tests, the probability that a person with a positive test is a true positive (i.e., has the disease), is referred to as the predictive value of a positive test; whereas, the predictive value of a negative test is the probability that the person with a negative test does not have the disease. Predictive value is related to the sensitivity and specificity of the test.

Differential regulation of Bcl-2, AP-1 and NF-kappaB on cardiomyocyte apoptosis during myocardial ischemic stress adaptation. (1/3052)

Acute ischemia followed by prolonged reperfusion has been shown to induce cardiomyocyte apoptosis. In this report, we demonstrate that myocardial adaptation to ischemia induced by repeated cyclic episodes of short-term ischemia each followed by another short duration of reperfusion reduced cardiomyocyte apoptosis and DNA fragmentation. This was associated with the induction of the expression of Bcl-2 mRNA and translocation and activation of NF-kappaB. Another transcription factor, AP-1, remained unaffected by repeated ischemia and reperfusion, but exhibited significant upregulation by a single episode of 30 min ischemia followed by 2 h of reperfusion. This activation of AP-1 was inhibited by a scavenger of oxygen free radicals, DMTU. Thirty minutes ischemia and 120 min reperfusion downregulated the induction of the expression of Bcl-2 mRNA, but moderately activated NF-kappaB binding activity. This was associated with an increased number of apoptotic cells and DNA fragmentation in cardiomyocytes which were attenuated by DMTU. The results of this study indicate that Bcl-2, AP-1 and NF-kappaB differentially regulate cardiomyocyte apoptosis mediated by acute ischemia and prolonged reperfusion.  (+info)

Reactive oxygen species play an important role in the activation of heat shock factor 1 in ischemic-reperfused heart. (2/3052)

BACKGROUND: The myocardial protective role of heat shock protein (HSP) has been demonstrated. Recently, we reported that ischemia/reperfusion induced a significant activation of heat shock factor (HSF) 1 and an accumulation of mRNA for HSP70 and HSP90. We examined the role of reactive oxygen species (ROSs) in the induction of stress response in the ischemic-reperfused heart. METHODS AND RESULTS: Rat hearts were isolated and perfused with Krebs-Henseleit buffer by the Langendorff method. Whole-cell extracts were prepared for gel mobility shift assay using oligonucleotides containing the heat shock element. Induction of mRNA for HSP70 and HSP90 was examined by Northern blot analysis. Repetitive ischemia/reperfusion, which causes recurrent bursts of free radical generation, resulted in burst activation of HSF1, and this burst activation was significantly reduced with either allopurinol 1 mmol/L (an inhibitor of xanthine oxidase) or catalase 2x10(5) U/L (a scavenger of H2O2). Significant activation of HSF1 was observed on perfusion with buffer containing H2O2 150 micromol/L or xanthine 1 mmol/L plus xanthine oxidase 5 U/L. The accumulation of mRNA for HSP70 or HSP90 after repetitive ischemia/reperfusion was reduced with either allopurinol or catalase. CONCLUSIONS: Our findings demonstrate that ROSs play an important role in the activation of HSF1 and the accumulation of mRNA for HSP70 and HSP90 in the ischemic-reperfused heart.  (+info)

Nonanticoagulant heparin prevents coronary endothelial dysfunction after brief ischemia-reperfusion injury in the dog. (3/3052)

BACKGROUND: Coronary endothelial dysfunction after brief ischemia-reperfusion (IR) remains a clinical problem. We investigated the role of heparin and N-acetylheparin, a nonanticoagulant heparin derivative, in modulating coronary endothelial function after IR injury, with an emphasis on defining the role of the nitric oxide (NO)-cGMP pathway in the heparin-mediated effect. METHODS AND RESULTS: Male mongrel dogs were surgically instrumented, and the effects of both bovine heparin and N-acetylheparin on coronary endothelial vasomotor function, expressed as percent change from baseline flow after acetylcholine challenge, were studied after 15 minutes of regional ischemia of the left anterior descending artery (LAD) followed by 120 minutes of reperfusion. In dogs treated with placebo (saline), coronary vasomotor function was significantly (P+info)

Tumor necrosis factor-alpha contributes to ischemia- and reperfusion-induced endothelial activation in isolated hearts. (4/3052)

-During myocardial reperfusion, polymorphonuclear neutrophil (PMN) adhesion involving the intercellular adhesion molecule-1 (ICAM-1) may lead to aggravation and prolongation of reperfusion injury. We studied the role of early tumor necrosis factor-alpha (TNF-alpha) cleavage and nuclear factor-kappaB (NF-kappaB) activation on ICAM-1 expression and venular adhesion of PMN in isolated hearts after ischemia (15 minutes) and reperfusion (30 to 480 minutes). NF-kappaB activation (electromobility shift assay) was found after 30 minutes of reperfusion and up to 240 minutes. ICAM-1 mRNA, assessed by Northern blot, increased during the same interval. Functional effect of newly synthesized adhesion molecules was found by quantification (in situ fluorescence microscopy) of PMN, given as bolus after ischemia, which became adherent to small coronary venules (10 to 50 microm in diameter). After 480 minutes of reperfusion, ICAM-1-dependent PMN adhesion increased 2.5-fold compared with PMN adhesion obtained during acute reperfusion. To study the influence of NF-kappaB on PMN adhesion, we inhibited NF-kappaB activation by transfection of NF-kappaB decoy oligonucleotides into isolated hearts using HJV-liposomes. Decoy NF-kappaB but not control oligonucleotides blocked ICAM-1 upregulation and inhibited the subacute increase in PMN adhesion. Similar effects were obtained using BB 1101 (10 microg), an inhibitor of TNF-alpha cleavage enzyme. These data suggest that ischemia and reperfusion in isolated hearts cause liberation of TNF-alpha, activation of NF-kappaB, and upregulation of ICAM-1, an adhesion molecule involved in inflammatory response after ischemia and reperfusion.  (+info)

Effects of isoproterenol on myocardial structure and function in septic rats. (5/3052)

In this study we sought to determine the effect of sepsis on two sequelae of prolonged (24-h) beta-agonist administration, myocardial hypertrophy and catecholamine-induced cardiotoxicity. Sprague-Dawley rats were randomized to cecal ligation and perforation (CLP) or sham study groups and then further randomized to receive isoproterenol (2.4 mg. kg-1. day-1 iv) or placebo treatment. At 24 h, myocardial function was assessed by using the Langendorff isolated-heart technique or the heart processed for plain light microscopy. We found that 1) sepsis reduced contractile function, indicated by a rightward shift in the Starling curve (ANOVA with repeated measures, sepsis effect, P < 0.002); 2) sepsis-induced myocardial depression was reversed by isoproterenol treatment (isoproterenol effect, P < 0.0001); 3) sepsis reduced, but did not block, isoproterenol-induced myocardial hypertrophy (isoproterenol effect, P < 0.0001); 4) sepsis did not protect the heart from catecholamine-induced tissue injury; 5) the septic heart was protected against the effects of ischemiareperfusion (decreased postreperfusion resting tension, ANOVA with repeated measures, P < 0.01), an effect attenuated by isoproterenol treatment (P < 0.005); and 6) sepsis reduced the incidence of sustained asystole or ventricular fibrillation after ischemia-reperfusion (P < 0.05), an effect also attenuated by isoproterenol treatment (P < 0.01). We conclude that, in sepsis, beta-agonists induce changes in myocardial weight and function consistent with acute myocardial hypertrophy. These changes occur at the expense of significant tissue injury and increased sensitivity to ischemia-reperfusion-induced tissue injury.  (+info)

Formation of 4-hydroxy-2-nonenal-modified proteins in ischemic rat heart. (6/3052)

4-Hydroxy-2-nonenal (HNE) is a major lipid peroxidation product formed during oxidative stress. Because of its reactivity with nucleophilic compounds, particularly metabolites and proteins containing thiol groups, HNE is cytotoxic. The aim of this study was to assess the extent and time course for the formation of HNE-modified proteins during ischemia and ischemia plus reperfusion in isolated rat hearts. With an antibody to HNE-Cys/His/Lys and densitometry of Western blots, we quantified the amount of HNE-protein adduct in the heart. By taking biopsies from single hearts (n = 5) at various times (0, 5, 10, 15, 20, 35, and 40 min) after onset of zero-flow global ischemia, we showed a progressive, time-dependent increase (which peaked after 30 min) in HNE-mediated modification of a discrete number of proteins. In studies with individual hearts (n = 4/group), control aerobic perfusion (70 min) resulted in a very low level (296 arbitrary units) of HNE-protein adduct formation; by contrast, after 30-min ischemia HNE-adduct content increased by >50-fold (15,356 units, P < 0.05). In other studies (n = 4/group), administration of N-(2-mercaptopropionyl)glycine (MPG, 1 mM) to the heart for 5 min immediately before 30-min ischemia reduced HNE-protein adduct formation during ischemia by approximately 75%. In studies (n = 4/group) that included reperfusion of hearts after 5, 10, 15, or 30 min of ischemia, there was no further increase in the extent of HNE-protein adduct formation over that seen with ischemia alone. Similarly, in experiments with MPG, reperfusion did not significantly influence the tissue content of HNE-protein adduct. Western immunoblot results were confirmed in studies using in situ immunofluorescent localization of HNE-protein in cryosections. In conclusion, ischemia causes a major increase in HNE-protein adduct that would be expected to reflect a toxic sequence of events that might act to compromise tissue survival during ischemia and recovery on reperfusion.  (+info)

Metallothionein inhibits ischemia-reperfusion injury in mouse heart. (7/3052)

Oxidative stress is believed to play a major role in ischemia-reperfusion injury to the heart. Metallothionein (MT), a potential free radical scavenger, may function in cardiac protection against ischemia-reperfusion damage. To test this hypothesis, a specific cardiac MT-overexpressing transgenic mouse model was used. The hearts isolated from these animals were subjected to 50 min of warm (37 degrees C) zero-flow ischemia followed by 60- or 90-min reflow. Compared with the nontransgenic controls, the transgenic mouse hearts with MT concentrations approximately 10-fold higher than normal showed significantly improved recovery of contractile force postischemia (69.2 +/- 4.2 vs. 26.0 +/- 6.0% at the end of 60-min reperfusion, P < 0.01). Efflux of creatine kinase from these transgenic hearts was reduced by more than 50% (P < 0.01). In addition, the zone of infarction induced by ischemia-reperfusion at the end of 90-min reperfusion was suppressed by approximately 40% (P < 0.01) in the transgenic hearts. The results strongly indicate that MT provides protection against ischemia-reperfusion-induced heart injury.  (+info)

Acute exercise can improve cardioprotection without increasing heat shock protein content. (8/3052)

The aim of this study was to determine the effects of acute bouts of exercise on myocardial recovery after ischemia and heat shock protein expression. Adult female Sprague-Dawley rats were divided into five groups: 1) 1-day run (1DR; n = 6) and 2) 3-day run (3DR; n = 7), in which rats ran for 100 min at a speed of 20 m/min up a 6 degrees grade for 1 or 3 consecutive days; 3) 1-day cold run (1CR), in which rats ran the same as 1DR but with wet fur at 8 degrees C, which prevented an elevation of core temperature (n = 8); 4) heat shock sedentary (HS), in which rats had their core temperatures raised to 42 degrees C one time for 15 min (n = 5); and 5) sedentary control (n=15). Cardiac function was analyzed 24 h after the last treatment using an isolated, working heart model. Nonpaced hearts were initially perfused under normoxic conditions, then underwent 17 min of global, normothermic (37 degrees C) ischemia, and, finally, were allowed to recover for 30 min under normoxic conditions. The concentration of the 72-kDa heat shock protein (HSP 72) was measured in each left ventricle. Compared with that in the sedentary group, recovery of cardiac output x systolic pressure (CO x SP) was enhanced (P < 0.05) in all treatment groups when the postischemic value was covaried with the preischemic value. No differences in CO x SP were found (P > 0.05) between the following groups: 1DR vs. 3DR, 1DR vs. HS, and 1DR vs. 1CR. Heat shock protein concentration was significantly greater (P < 0.05) than that in the sedentary controls in HS, 1DR, and 3DR groups, but not for 1CR. The concentration of HSP 72 was not significantly correlated with postischemic CO x SP (R2 = 0.197, P > 0.05). We conclude that acute bouts of exercise can produce cardioprotective effects without an elevation of HSP 72.  (+info)

  • The present study demonstrates that renal dysfunction increases cardiac susceptibility to ischemic-reperfusion injury, which is associated with downregulated APN/AdipoR1/AMPK signaling and increased oxidative/nitrative stress in local myocardium, and provides the first evidence for the protective role of exogenous supplement of gAd on MI/R outcomes in renal failure. (
  • Perfusate proteins were separated using two-dimensional gel electrophoresis (2-DE) and identified by mass spectrometry (MS), revealing 26 tissue-specific proteins released during reperfusion post-15I. (
  • A total of 192 tissue-specific proteins were identified during reperfusion post-60I. (
  • Debate has gone on, and continues regarding the existence of reperfusion injury and the pathways that are solicited. (
  • The present study was designed to investigate the specific role of IL‑23 in myocardial I/R injury, and whether the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2‑STAT3) signaling pathway, one of the important downstream signaling pathways of IL‑23, and the IL‑17A downstream pro‑inflammatory cytokine, were involved. (
  • Moreover, SN increased myocardial NO metabolites, superoxide, and their cytotoxic reaction product peroxynitrite, upregulated inducible NO synthase expression, and decreased endothelial NOS phosphorylation. (
  • During the development of I/R injury, a surge of reactive oxygen and nitrogen species as well as inflammatory cascades bursts and eventually triggers organ damage [ 3 ]. (
  • Four weeks later anesthetized animals were subjected to total occlusion (45 minutes) of the left main coronary artery followed by 5 hours of reperfusion. (
  • microRNA 223-3p and microRNA 3113-5p were among the mostly altered microRNAs and were validated to be up-regulated within the early hours of I/R injury in heart tissues. (
  • So far, more than 200 microRNAs have been considered as heart-specific with many of them being identified to release into the circulatory system during ischemic injury. (