Cyclophilin D and myocardial ischemia–reperfusion injury: A fresh perspective

Alam, Muhammad Rizwan; Baetz, Delphine; Ovize, Michel

doi:10.1016/j.yjmcc.2014.09.026

Cited by 81 publications

(69 citation statements)

References 150 publications

(222 reference statements)

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“…303,317 Cyclosporine A is a drug which inhibits cyclophilin D, can thus inhibit MPTP opening, and ultimately also reduce IS in experimental studies, [318][319][320][321][322] but also in humans with reperfused AMI 323 and elective coronary artery bypass grafting. 324 The MPTP not only plays a central role in mitochondrial and cellular death or survival, but is also a point of convergence of cardioprotective signaling.…”

Section: Mitochondrial Permeability Transition Porementioning

confidence: 99%

Molecular Basis of Cardioprotection

Heusch

2015

Circulation Research

702

409

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Abstract:Reperfusion is mandatory to salvage ischemic myocardium from infarction, but reperfusion per se contributes to injury and ultimate infarct size. Therefore, cardioprotection beyond that by timely reperfusion is needed to reduce infarct size and improve the prognosis of patients with acute myocardial infarction. The conditioning phenomena provide such cardioprotection, insofar as brief episodes of coronary occlusion/ reperfusion preceding (ischemic preconditioning) or following (ischemic postconditioning) sustained myocardial ischemia with reperfusion reduce infarct size. Even ischemia/reperfusion in organs remote from the heart provides cardioprotection (remote ischemic conditioning). The present review characterizes the signal transduction underlying the conditioning phenomena, including their physical and chemical triggers, intracellular signal transduction, and effector mechanisms, notably in the mitochondria. Cardioprotective signal transduction appears as a highly concerted spatiotemporal program. Although the translation of ischemic postconditioning and remote ischemic conditioning protocols to patients with acute myocardial infarction has been fairly successful, the pharmacological recruitment of cardioprotective signaling has been largely disappointing to date.

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Section: Mitochondrial Permeability Transition Porementioning

confidence: 99%

Molecular Basis of Cardioprotection

Heusch

2015

Circulation Research

702

409

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“…This is interesting as it indicates that much of the oxidative damage is survivable, if cell death due to MPTP activation is prevented. In fact, there are some promising indications that cyclophilin D inhibitors, such as cyclosporine, could reduce infarct size in humans [38,39]. However, limiting oxidative stress during reperfusion will help to contain the mitochondrial damage and the recovery of the surviving cells [40].…”

Section: +mentioning

confidence: 99%

The role of mitochondria in cardiac development and protection

Pohjoismäki

Goffart

2017

Free Radical Biology and Medicine

101

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Mitochondria are essential for the development as well as maintenance of the myocardium, the most energy consuming tissue in the human body. Mitochondria are not only a source of ATP energy but also generators of reactive oxygen species (ROS), that cause oxidative damage, but also regulate physiological processes such as the switch from hyperplastic to hypertrophic growth after birth. As excess ROS production and oxidative damage are associated with cardiac pathology, it is not surprising that much of the research focused on the deleterious aspects of free radicals. However, cardiomyocytes are naturally highly adapted against repeating oxidative insults, with evidence suggesting that moderate and acute ROS exposure has beneficial consequences for mitochondrial maintenance and cardiac health. Antioxidant defenses, mitochondrial quality control, mtDNA maintenance mechanisms as well as mitochondrial fusion and fission improve mitochondrial function and cardiomyocyte survival under stress conditions. As these adaptive processes can be induced, promoting mitohormesis or mitochondrial biogenesis using controlled ROS exposure could provide a promising strategy to increase cardiomyocyte survival and prevent pathological remodeling of the myocardium.

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“…And recent researches have confirmed that inhibiting mPTP opening at reperfusion could protect against IRI (38,39). Furthermore, it is thought that mPTP is the ultimate determinant of myocardial cell apoptosis (21)(22)(23) and it is the key mechanism of many different types of cardioprotective methods (24)(25)(26)(27). So we speculated the mechanism of cardioprotection from the inhibitor of GSK-3β which is highly possible associated with reducing the irreversibly high level opening of mPTP and activating the apoptotic pathways in turn that aggravates myocardial IRI.…”

Section: Discussionmentioning

confidence: 96%

“…The high level irreversible opening of mPTP is another important mechanism of IRI. Past and recent researches definitely established that mPTP is the ultimate determinant of myocardial cell apoptosis (21)(22)(23) and it is the key mechanism of many different types of cardioprotective methods, such as preconditioning, postconditioning and some pharmacological postconditioning (24)(25)(26)(27).…”

mentioning

confidence: 99%

Glycogen Synthase Kinase 3β Inhibition Protects the Cardiomyocytes from Anoxia/Reoxygenation Injury by Modulating Inﬂammatory Response and Reducing the Opening of mPTP

Cheng¹,

Jun²,

Xue³

et al. 2015

J Anesth Perioper Med

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Background: Phosphorylation of glycogen synthase kinase 3β (GSK-3β) is crucial in multiple cardioprotective signaling pathways. But the downstream mechanism is unclear. Considering GSK-3β is the key regulator of nuclear factor-κB (NF-κB) and mitochondrial permeability transition pore (mPTP) is a critical determinant of lethal reperfusion injury, we assessed the mechanism of postconditioning with the selective inhibitor of GSK-3β associated with modulating in fl ammatory response and reducing the opening of mPTP. Methods: After cultured for 72 hours, neonatal rat cardiomyocytes were randomly divided into 3 groups according to random number table: Sham group, anoxia/reoxygenation injury group (AR group) and GSK-3β inhibitor TDZD -8 postconditioning group (TDZD -8 group). At the end of the experiment, the lactate dehydrogenase (LDH) release rate, myocardial apoptosis and the supernatant concentrations of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured. The NF-κBp65 and phosphorylated NF-κBp65Ser536 in all samples were assessed by western-blotting technique. The mitochondrial membrane potential was measured by rhodamine 123 staining flow cytometry and confocal laser scanning microscope. Results: We discovered that postconditioning with GSK-3β inhibitor TDZD -8 could significantly protect against cardiomyocyte anoxia/reoxygenation injury, as shown by reducing the early apoptosis and LDH release rate. And this cardioprotective method could significantly attenuate inflammatory response to the anoxia/reoxygenation injury, as evidenced by decreasing the activity of NF-κB and levels of inflammatory cytokines, such as IL-6 and TNF-α. Furthermore, it could significantly reduce the irreversibly high level opening of the mPTP, as evidenced by increasing the mitochondrial membrane potential of anoxia/reoxygenation cardiomyocyte. Conclusions: Our current results indicated that postconditioning with GSK-3β inhibitor TDZD -8 significantly attenuated the systemic inflammatory and reduced the opening of mPTP response to cardiomyocytes anoxia/reoxygenation injury.

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Cyclophilin D and myocardial ischemia–reperfusion injury: A fresh perspective

Cited by 81 publications

References 150 publications

Molecular Basis of Cardioprotection

Molecular Basis of Cardioprotection

The role of mitochondria in cardiac development and protection

Glycogen Synthase Kinase 3β Inhibition Protects the Cardiomyocytes from Anoxia/Reoxygenation Injury by Modulating Inﬂammatory Response and Reducing the Opening of mPTP

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