Mitochondrial Mechanism Underlying Morphine's Cardioprotection Against Ischemia/reperfusion Injury
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In recent years the main idea has been that reactive oxygen species (ROS) play an essential,though double-edged, role in cardioprotection: they may participate in reperfusion injury or may play a role as signaling elements during myocardial adaptation to ischemia. It has been demonstrated that pre-or postconditioning triggering is redox-sensitive, via a mitochondrial KATP-ROS-dependent mechanism.In these cardioprotective phenomenon a redox signal and inhibition of mPTP are required during myocardial reperfusion following the index ischemic period. Therefore, the role of ROS in reperfusion may be reconsidered as they are not only deleterious.
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Reactive oxygen species; Myocardial reperfusion injury; Mitochondria; Preconditioning; Postconditioning
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Background: Mitochondria (MITO) injury plays a major role in the mechanism of myocardial ischemia-reperfusion (IR) injury. Intravenous administration of an inhibitor of MITO permeability transition pore (mPTP) opening, cyclosporine A, at the time of reperfusion can reduce IR injury in animals and patients with acute myocardial infarction (MI), however; the degrees of cardioprotection induced by cyclosporine A seem to be inadequate. Therefore, a more effective modality for inhibiting MITO injury must be developed for cardioprotection from IR injury in acute MI. Here we tested the hypothesis that nanoparticle-mediated targeting of mitochondrial division inhibitor-1 (mdivi-1) to MITO enhances cardioprotection from IR injury.
Methods and Results: We formulated poly(lactic acid/glycolic acid) (PLGA) nanoparticles containing mdivi-1 (Mdivi1-NP) or FITC (FITC-NP). In neonatal rat cardiomyocytes, mitochondrial-targeting of nanoparticles was noted after the addition of hydrogen peroxide (H2O2) that represents oxidative stress during IR (Fig. A). Treatment with Mdivi1-NP (containing 5 μM mdivi-1) markedly attenuated H2O2-induced MITO-division and cardiomyocyte death (Fig. B). In Langendorff perfused mouse heart, treatment with Mdivi1-NP (5 and 50 μM) at the time of reperfusion enhanced the cardioprotection against IR injury achieved by mdivi1 alone (Fig. C). In an in vivo murine model of IR, treatment with Mdivi1-NP (1.2 mg/kg) at the time of reperfusion also enhanced the cardioprotection against IR injury achieved by mdivi1 alone. Interestingly, treatment with Mdivi1-NP reduced IR injury and MITO swelling in mice lacking cyclophilin D (a key regulatory molecule for mPTP opening) (Fig. D).
Conclusions: Nanoparticle-mediated targeting of mdivi1 to the mitochondria enhanced cardioprotection against IR injury through mechanisms independent of mPTP opening. Mdivi1-NP can be developed as a new cardioprotective strategy in acute MI.
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Early restoration of blood flow to the ischemic myocardium not only saves myocardium but also induces reperfusion injury. While no specific therapy to reduce reperfusion injury has yet been established, recent laboratory studies have shown that G protein-coupled receptor (GPCR) agonists, insulin, and postconditioning can effectively prevent reperfusion injury in various experimental settings and animal species. The potential mechanisms underlying the cardioprotection initiated by these interventions may include activation of the reperfusion injury salvage kinase (RISK) pathway, inactivation of glycogen synthase kinase 3beta (GSK-3beta), and modulation of mitochondrial permeability transition pore (mPTP) opening. These encouraging laboratory findings may help us develop successful clinical strategies to salvage reperfused myocardium in patients with acute myocardial infarction.
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While it is well known that endoplasmic reticulum stress (ERS) plays an important role in myocardial ischemia/reperfusion (I/R) injury and inhibition of ERS leads to cardioprotection against I/R in...
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Despite tremendous advances in cardiovascular research and clinical therapy, ischemic heart disease remains the leading cause of serious morbidity and mortality in western society and is growing in developing countries. For the past 5 decades, many scientists have studied the pathophysiology of myocardial ischemia-reperfusion (I/R) injury leading to infarction. With the exception of reperfusion therapy, attempts to salvage the myocardium during an acute myocardial infarction showed disappointing results in directly decreasing infarct size. Nevertheless, the phenomena of ischemic preconditioning and ischemic postconditioning show a consistent and robust cardioprotective effect in every used experimental animal model. As a result, many studies have focused on the intracellular protective signaling pathways that are involved in preconditioning and postconditioning. More recently, it has been suggested that components of the reperfusion injury salvage kinases pathway, protein kinase B, and the extracellular signal-regulated kinases can induce cardioprotection against I/R injury when they are activated during the postischemic reperfusion period. In addition, inhibition of mitochondrial permeability transition during postischemic reperfusion also shows a strong cardioprotective effect against I/R injury. The present mini-review highlights a short summary of the historical and present course of research into cardioprotection against myocardial I/R injury.
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Abstract Ischemic myocardium cannot survive without reperfusion. However, reperfusion of the ischemic myocardium paradoxically induces myocyte death; this phenomenon is termed lethal reperfusion injury. To date, no effective approach has been demonstrated for ST-segment elevation myocardial infarction (STEMI) in clinical settings. Recently, we demonstrated a novel approach for cardioprotection, termed postconditioning with lactate-enriched blood (PCLeB). PCLeB comprises intermittent reperfusion and timely coronary injections of lactated Ringer’s solution, which is implemented at the beginning of reperfusion. This approach is aimed at reducing lethal reperfusion injury via prolonging intracellular acidosis during the early period of reperfusion, compared with the original postconditioning protocol. Patients with STEMI treated using PCLeB have reported positive outcomes. This article represents an effort, with a perspective different from current insights, toward preventing lethal reperfusion injury, in light of the historical background of reperfusion injury research. PCLeB is considered the new approach for cardioprotection. Graphical Abstract
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Objective:The retina ischemia-reperfusion injury is caused by many factors. A lot of cell factors take part in it. Many researches suggest MCP-1 has special effect on leukocyte and lymphocyte.The research try to study the effect of MCP-1 in rat's retina ischemia-reperfusion injury.Methods:To employ the rat's retina ischemia-reperfusion model and use SABC method to test the expression of MCP-1 on retina.Results:There was no MCP-1 expressed in retina after ischemia-reperfusion injury for one hour. MCP-1 began to express in retina after ischemia-reperfusion injury for six hours, and expressed at most after ischemia-reperfusion injury for 24 hours. Then it began to decrease in 48 hours after ischemia-reperfusion injury, but it still expressed in retina in seventy-two hours after ischemia-reperfusion injury.Conclusions:MCP-1 plays an important role in rat's retina ischemia-reperfusion injury.
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During the past decade, the understanding has grown that control of the conditions of reperfusion is critical for salvaging ischemic-reperfused myocardium. The first few minutes of reperfusion constitute a critical phase, as here lethal tissue injury in addition to that already developed during ischemia may be initiated. The identification of the mechanisms of reperfusion-induced cell death opens a new window of opportunity for cardioprotection in the clinic. Development of cardiomyocyte hypercontracture is a predominant feature of reperfusion injury. We and others have shown that control of hypercontracture in reperfusion reduces the extent of tissue injury. On the cellular level, it was shown that reperfusion-induced hypercontracture might either originate from a rigor-type mechanism, when energy recovery proceeds very slowly, or from Ca2+ overload, when energy recovery is rapid but cytosolic Ca2+ load is high. These two mechanisms can be influenced by various interventions that either connect with cytosolic Ca2+ control or myofibrillar Ca2+ sensitivity or with mitochondrial energy production. These experimental approaches will hopefully lead to novel strategies for clinical cardioprotection during the early phase of reperfusion.
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