scholarly journals Melatonin Attenuates Cardiac Ischemia-Reperfusion Injury through Modulation of IP3R-Mediated Mitochondria-ER Contact

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Wenya Li ◽  
Botao Liu ◽  
Lin Wang ◽  
Jilie Liu ◽  
Xiuhui Yang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Cardiac Cells ◽  
Mitochondrial Potential ◽  
Rat Cardiomyocytes ◽  
Postischemic Reperfusion

Although the interplay between mitochondria and ER has been identified as a crucial regulator of cellular homeostasis, the pathogenic impact of alterations in mitochondria-ER contact sites (MERCS) during myocardial postischemic reperfusion (I/R) injury remains incompletely understood. Therefore, in our study, we explored the beneficial role played by melatonin in protecting cardiomyocytes against reperfusion injury via stabilizing mitochondria-ER interaction. In vitro exposure of H9C2 rat cardiomyocytes to hypoxia/reoxygenation (H/R) augmented mitochondrial ROS synthesis, suppressed both mitochondrial potential and ATP generation, and increased the mitochondrial permeability transition pore (mPTP) opening rate. Furthermore, H/R exposure upregulated the protein content of CHOP and caspase-12, two markers of ER stress, and enhanced the transcription of main MERCS tethering proteins, namely, Fis1, BAP31, Mfn2, and IP3R. Interestingly, all the above changes could be attenuated or reversed by melatonin treatment. Suggesting that melatonin-induced cardioprotection works through normalization of mitochondria-ER interaction, overexpression of IP3R abolished the protective actions offered by melatonin on mitochondria-ER fitness. These results expand our knowledge on the cardioprotective actions of melatonin during myocardial postischemic reperfusion damage and suggest that novel, more effective treatments for acute myocardial reperfusion injury might be achieved through modulation of mitochondria-ER interaction in cardiac cells.

Past and present course of cardioprotection against ischemia- reperfusion injury

2007 ◽  
Vol 103 (6) ◽  
pp. 2129-2136 ◽  
Author(s):  
David A. Liem ◽  
Henry M. Honda ◽  
Jun Zhang ◽  
David Woo ◽  
Peipei Ping
Keyword(s):  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Reperfusion Therapy ◽  
Cardioprotective Effect ◽  
Western Society ◽  
Cardiovascular Research ◽  
Postischemic Reperfusion

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.

scholarly journals Multidimensional Regulation of Cardiac Mitochondrial Potassium Channels

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1554
Author(s):  
Bogusz Kulawiak ◽  
Piotr Bednarczyk ◽  
Adam Szewczyk
Keyword(s):  
Potassium Channels ◽  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Current Knowledge ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Cardiac Cells ◽  
Cardiac Ischemia ◽  
Inner Mitochondrial Membrane

Mitochondria play a fundamental role in the energetics of cardiac cells. Moreover, mitochondria are involved in cardiac ischemia/reperfusion injury by opening the mitochondrial permeability transition pore which is the major cause of cell death. The preservation of mitochondrial function is an essential component of the cardioprotective mechanism. The involvement of mitochondrial K+ transport in this complex phenomenon seems to be well established. Several mitochondrial K+ channels in the inner mitochondrial membrane, such as ATP-sensitive, voltage-regulated, calcium-activated and Na+-activated channels, have been discovered. This obliges us to ask the following question: why is the simple potassium ion influx process carried out by several different mitochondrial potassium channels? In this review, we summarize the current knowledge of both the properties of mitochondrial potassium channels in cardiac mitochondria and the current understanding of their multidimensional functional role. We also critically summarize the pharmacological modulation of these proteins within the context of cardiac ischemia/reperfusion injury and cardioprotection.

scholarly journals The cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia–reperfusion in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Khairat Bahgat Youssef El Baradie ◽  
Mohammad B. Khan ◽  
Bharati Mendhe ◽  
Jennifer Waller ◽  
Frederick O’Brien ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Survival ◽  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Mitochondrial Permeability

AbstractAcute ischemia–reperfusion injury in skeletal muscle is a significant clinical concern in the trauma setting. The mitochondrial permeability transition inhibitor NIM-811 has previously been shown to reduce ischemic injury in the liver and kidney. The effects of this treatment on skeletal muscle are, however, not well understood. We first used an in vitro model of muscle cell ischemia in which primary human skeletal myoblasts were exposed to hypoxic conditions (1% O2 and 5% CO2) for 6 h. Cells were treated with NIM-811 (0–20 µM). MTS assay was used to quantify cell survival and LDH assay to quantify cytotoxicity 2 h after treatment. Results indicate that NIM-811 treatment of ischemic myotubes significantly increased cell survival and decreased LDH in a dose-dependent manner. We then examined NIM-811 effects in vivo using orthodontic rubber bands (ORBs) for 90 min of single hindlimb ischemia. Mice received vehicle or NIM-811 (10 mg/kg BW) 10 min before reperfusion and 3 h later. Ischemia and reperfusion were monitored using laser speckle imaging. In vivo data demonstrate that mice treated with NIM-811 showed increased gait speed and improved Tarlov scores compared to vehicle-treated mice. The ischemic limbs of female mice treated with NIM-811 showed significantly lower levels of MCP-1, IL-23, IL-6, and IL-1α compared to limbs of vehicle-treated mice. Similarly, male mice treated with NIM-811 showed significantly lower levels of MCP-1 and IL-1a. These findings are clinically relevant as MCP-1, IL-23, IL-6, and IL-1α are all pro-inflammatory factors that are thought to contribute directly to tissue damage after ischemic injury. Results from the in vitro and in vivo experiments suggest that NIM-811 and possibly other mitochondrial permeability transition inhibitors may be effective for improving skeletal muscle salvage and survival after ischemia–reperfusion injury.

scholarly journals Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

2015 ◽  
Vol 112 (17) ◽  
pp. E2253-E2262 ◽  
Author(s):  
Youn Wook Chung ◽  
Claudia Lagranha ◽  
Yong Chen ◽  
Junhui Sun ◽  
Guang Tong ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mouse Heart ◽  
Targeted Disruption

Although inhibition of cyclic nucleotide phosphodiesterase type 3 (PDE3) has been reported to protect rodent heart against ischemia/reperfusion (I/R) injury, neither the specific PDE3 isoform involved nor the underlying mechanisms have been identified. Targeted disruption of PDE3 subfamily B (PDE3B), but not of PDE3 subfamily A (PDE3A), protected mouse heart from I/R injury in vivo and in vitro, with reduced infarct size and improved cardiac function. The cardioprotective effect in PDE3B−/− heart was reversed by blocking cAMP-dependent PKA and by paxilline, an inhibitor of mitochondrial calcium-activated K channels, the opening of which is potentiated by cAMP/PKA signaling. Compared with WT mitochondria, PDE3B−/− mitochondria were enriched in antiapoptotic Bcl-2, produced less reactive oxygen species, and more frequently contacted transverse tubules where PDE3B was localized with caveolin-3. Moreover, a PDE3B−/− mitochondrial fraction containing connexin-43 and caveolin-3 was more resistant to Ca2+-induced opening of the mitochondrial permeability transition pore. Proteomics analyses indicated that PDE3B−/− heart mitochondria fractions were enriched in buoyant ischemia-induced caveolin-3–enriched fractions (ICEFs) containing cardioprotective proteins. Accumulation of proteins into ICEFs was PKA dependent and was achieved by ischemic preconditioning or treatment of WT heart with the PDE3 inhibitor cilostamide. Taken together, these findings indicate that PDE3B deletion confers cardioprotective effects because of cAMP/PKA-induced preconditioning, which is associated with the accumulation of proteins with cardioprotective function in ICEFs. To our knowledge, our study is the first to define a role for PDE3B in cardioprotection against I/R injury and suggests PDE3B as a target for cardiovascular therapies.

scholarly journals The Role of O-GlcNAcylation for Protection against Ischemia-Reperfusion Injury

2019 ◽  
Vol 20 (2) ◽  
pp. 404 ◽  
Author(s):  
Rebekka Jensen ◽  
Ioanna Andreadou ◽  
Derek Hausenloy ◽  
Hans Bøtker
Keyword(s):  
Reperfusion Injury ◽  
Ischemic Preconditioning ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mechanical Conditioning ◽  
Cell Functions ◽  
Heat Shock Responses

Ischemia reperfusion injury (IR injury) associated with ischemic heart disease contributes significantly to morbidity and mortality. O-linked β-N-acetylglucosamine (O-GlcNAc) is a dynamic posttranslational modification that plays an important role in numerous biological processes, both in normal cell functions and disease. O-GlcNAc increases in response to stress. This increase mediates stress tolerance and cell survival, and is protective. Increasing O-GlcNAc is protective against IR injury. Experimental cellular and animal models, and also human studies, have demonstrated that protection against IR injury by ischemic preconditioning, and the more clinically applicable remote ischemic preconditioning, is associated with increases in O-GlcNAc levels. In this review we discuss how the principal mechanisms underlying tissue protection against IR injury and the associated immediate elevation of O-GlcNAc may involve attenuation of calcium overload, attenuation of mitochondrial permeability transition pore opening, reduction of endoplasmic reticulum stress, modification of inflammatory and heat shock responses, and interference with established cardioprotective pathways. O-GlcNAcylation seems to be an inherent adaptive cytoprotective response to IR injury that is activated by mechanical conditioning strategies.

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