Abstract 12375: Inhibition of ERS Leads to Cardioprotection against Ischemia Reperfusion Injury by Preventing the mPTP Opening
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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...Keywords:
Cardioprotection
MPTP
Myocardial Reperfusion Injury
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We aimed to investigate whether the cardioprotection of sevoflurane against ischemia-reperfusion (IR) injury is via inhibiting endoplasmic reticulum stress. The rat in vivo model of myocardial IR injury was induced by ligation of the left anterior descending coronary artery. Sevoflurane significantly ameliorated the reduced cardiac function, increased infarct size, and elevated troponin I level and lactate dehydrogenase activity in plasma induced by IR injury. Sevoflurane suppressed the IR-induced myocardial apoptosis. The increased protein levels of glucose-regulated protein 78 and C/EBP homologous protein (CHOP) after myocardial IR were significantly reduced by sevoflurane. The protein levels of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (PERK), phosphorylated eukaryotic initiation factor 2 (eIF2α), and activating transcription factor 4 (ATF4) were significantly increased in rats with IR and attenuated by sevoflurane treatment. The phosphorylation of Akt was further activated by sevoflurane. The cardioprotection of sevoflurane could be blocked by wortmannin, a PI3K/Akt inhibitor. Our results suggest that the cardioprotection of sevoflurane against IR injury might be mediated by suppressing PERK/eIF2a/ATF4/CHOP signaling via activating the Akt pathway, which helps in understanding the novel mechanism of the cardioprotection of sevoflurane.
Cardioprotection
Wortmannin
Caspase 12
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Recent studies indicate that cell apoptosis is closely related to myocardial ischemia/reperfusion injury, and may be involved in its pathogenesis. This article reviews the mechanisms, control genes and signalling pathways mediating cardiomyocyte apoptosis in myocardial ischemia/reperfusion injury.
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Background: Mitochondrial dysfunction and inappropriate mitophagy contribute to myocardial ischemia/reperfusion (MI/R) injury. The cardiokine CTRP9 exerts protective effect against myocardial ische...
Cardioprotection
Myocardial Reperfusion Injury
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Introduction: RISK is the main cardioprotective pathway against ischemia-reperfusion (I-R) injury, and starts with the phosphorylation (activation) of Akt. Phosphatase and tensin homolog deleted on...
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Although morphine has been demonstrated to protect the heart from ischemia/reperfusion injury through various signaling mechanisms, the signaling events occurring within mitochondria that mediate m...
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Introduction: Myocardial reperfusion injury underlies half of final infarct size following myocardial infarction and, so far, no effective therapy has been demonstrated. Modulation of mitochondrial...
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Signalling
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Background: Mitochondria (MITO) injury including MITO permeability transition pore (mPTP) opening plays a major role in the mechanism of ischemia-reperfusion (IR) injury. Intravenous administration of an inhibitor of mPTP opening, cyclosporine A, can reduce IR injury in animals and patients with acute myocardial infarction (MI), however; the power of cardioprotection by cyclosporine A is insufficient. We tested the hypothesis that nanoparticle-mediated targeting of Mdivi1, a chemical inhibitor of Drp1, to MITO enhances cardioprotection from IR injury. Methods and Results: We formulated poly(lactic acid/glycolic acid) (PLGA) nanoparticles containing Mdivi1 (Mdivi1-NP) or FITC (FITC-NP). In neonatal rat cardiomyocytes, PLGA nanoparticles accumulated in MITO after the addition of hydrogen peroxide (H2O2) that represents oxidative stress during IR (Fig.A). Treatment with Mdivi1-NP reduced H2O2-induced MITO division and cardiomyocyte death (Fig.B). This Mdivi1-NP cardioprotective effect was not seen over adenovirus harboring Drp1 shRNA transduced cardiomyocyte. In an in vivo and ex vivo murine model, treatment with Mdivi1-NP at the time of reperfusion reduced infarct size more effectively than Mdivi1 alone (Fig.C). Interestingly, Mdivi1-NP inhibited the leakage of cytochrome c to cytosol and MITO swelling, and reduced IR injury in both wildtype and cyclophilin D (a key regulatory molecule for mPTP opening)-KO mice (Fig.D). Conclusions: Mdivi1-NP enhanced cardioprotection against IR injury through mechanisms independent of mPTP opening. Mdivi1-NP can be a novel cardioprotective strategy in acute MI.
Cardioprotection
MPTP
Ex vivo
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