Naringin attenuates rat myocardial ischemia/reperfusion injury via PI3K/Akt pathway‑mediated inhibition of apoptosis, oxidative stress and autophagy
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Naringin (NRG) has been reported to exert cardioprotective effects against multiple cardiovascular diseases, including lipopolysaccharide‑induced and hyperglycemia‑induced myocardial injury. However, the role of NRG in myocardial ischemia/reperfusion (I/R) injury remains unclear. In the present study, the PI3K/Akt pathway was investigated to evaluate the possible mechanisms underlying the roles of NRG in myocardial ischemia/reperfusion (I/R) injury. The levels of cardiac enzymes were measured by ELISA to evaluate the optimal dosage of NRG that could protect against myocardial I/R injury. Rats were administered 100 mg/kg of NRG and activities of myocardial enzymes, the level of cardiac apoptosis and inflammation, oxidant response, autophagy indicators and echocardiography were evaluated. The level of corresponding proteins was measured using western blotting. The results indicated that NRG elicited the best cardioprotective effects at a dose of 100 mg/kg by significantly reducing the levels of myocardial enzymes, apoptosis, inflammation, oxidative response and infarct size. Furthermore, NRG alleviated contractile dysfunction by increasing the left ventricular ejection fraction and fractional shortening. In addition, NRG markedly promoted the phosphorylation of Akt, while decreasing the level of autophagy indicator beclin‑1 and the microtubule‑associated protein 1B‑light chain 3 (LC3B) II/ LC3BI ratio. However, PI3K/Akt inhibitor (LY294002) partially reduced the NRG induced phosphorylation of Akt and the reduction in beclin‑1, along with the LC3BII/LC3BI ratio. The results of the present study demonstrated that NRG could attenuate myocardial I/R injury.Keywords:
Naringin
Cardioprotection
Based on growing evidence linking autophagy to preconditioning, we tested the hypothesis that autophagy is necessary for cardioprotection conferred by ischemic preconditioning (IPC). We induced IPC with three cycles of 5 min regional ischemia alternating with 5 min reperfusion and assessed the induction of autophagy in mCherry-LC3 transgenic mice by imaging of fluorescent autophagosomes in cryosections. We found a rapid and significant increase in the number of autophagosomes in the risk zone of the preconditioned hearts. In Langendorff-perfused hearts subjected to an IPC protocol of 3 x 5 min ischemia, we also observed an increase in autophagy within 10 min, as assessed by Western blotting for p62 and cadaverine dye binding. To establish the role of autophagy in IPC cardioprotection, we inhibited autophagy with Tat-ATG5(K130R), a dominant negative mutation of the autophagy protein Atg5. Cardioprotection by IPC was reduced in rat hearts perfused with recombinant Tat-ATG5(K130R). To extend the potential significance of autophagy in cardioprotection, we also assessed three structurally unrelated cardioprotective agents--UTP, diazoxide, and ranolazine--for their ability to induce autophagy in HL-1 cells. We found that all three agents induced autophagy; inhibition of autophagy abolished their protective effect. Taken together, these findings establish autophagy as an end-effector in ischemic and pharmacologic preconditioning.
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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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Background Autophagy is one of the most attractive research fields in recent years. It has been found to be extensively related to myocardial ischemia reperfusion injury. Purpose This article outlines the recent progresses in the research on autophagy. Content To elucidate the classification of autophagy, its character and the detection method, as well as the relationship between autohagy and myocardial reperfusion injury, including the inducement mechanism of it. Trend The further understanding of the relationship between autophagy and reperfusion injury and the underlying mechanism is still to be elucidated,and the extent of benefitial induction of autophagy to protect myocardium from reperfusion injury is still to be decided.
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Autophagy; Schemia/reperfusion injury
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Treatment of Myocardial Ischemia/Reperfusion Injury by Ischemic and Pharmacological Postconditioning
Timely reperfusion is the only way to salvage ischemic myocardium from impending infarction. However, reperfusion also adds a further component to myocardial injury such that the ultimate infarct size is the result of both ischemia- and reperfusion-induced injury. Modification of reperfusion can attenuate reperfusion injury and thus reduce infarct size. Ischemic postconditioning is a maneuver of repeated brief interruption of reperfusion by short-lasting coronary occlusions which results in reduced infarct size. Cardioprotection by ischemic postconditioning is mediated through delayed reversal of acidosis and the activation of a complex signal transduction cascade, including triggers such as adenosine, bradykinin, and opioids, mediators such as protein kinases and, notably, mitochondrial function as effector. Inhibition of the mitochondrial permeability transition pore appears to be a final signaling step of ischemic postconditioning. Several drugs which recruit in part such signaling steps of ischemic postconditioning can induce cardioprotection, even when the drug is only administered at reperfusion, that is, there is also pharmacological postconditioning. Ischemic and pharmacological postconditioning have been translated to patients with acute myocardial infarction in proof-of-concept studies, but further mechanistic insight is needed to optimize the conditions and algorithms of cardioprotection by postconditioning. © 2015 American Physiological Society. Compr Physiol 5:1123-1145, 2015.
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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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Myocardial 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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Background: Akt is an important signaling molecule that modulates many cellular processes such as cell growth, survival and metabolism. Akt activation has been proposed as a potential strategy for increasing cardiomyocyte survival following ischemia. Objectives: Vanadium compounds activate Akt signaling through inhibition of protein tyrosine phosphatases, thereby eliciting cardioprotection in myocardial ischemia/reperfusion-induced injury along with cardiac functional recovery. Like other vanadium compounds, we documented bis(1-oxy-2-pyridinethiolato) oxovanadium (IV) as a potent cytoprotective agent on myocardial infarction and elicited cardiac functional recovery through activation of Akt signaling pathway. Results/conclusion: The ability of vanadium compounds to activate Akt signaling pathways are responsible for their ability to modulate cardiovascular functions and is probably beneficial as a cardioprotective drug in subjects undergoing reperfusion therapy following myocardial infarction.
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