Dataset Information

Acute Induction of Translocon-Mediated Ca²⁺ Leak Protects Cardiomyocytes Against Ischemia/Reperfusion Injury.

ABSTRACT: During myocardial infarction, dysregulation of Ca²⁺ homeostasis between the reticulum, mitochondria, and cytosol occurs in cardiomyocytes and leads to cell death. Ca²⁺ leak channels are thought to be key regulators of the reticular Ca²⁺ homeostasis and cell survival. The present study aimed to determine whether a particular reticular Ca²⁺ leak channel, the translocon, also known as translocation channel, could be a relevant target against ischemia/reperfusion-mediated heart injury. To achieve this objective, we first used an intramyocardial adenoviral strategy to express biosensors in order to assess Ca²⁺ variations in freshly isolated adult mouse cardiomyocytes to show that translocon is a functional reticular Ca²⁺ leak channel. Interestingly, translocon activation by puromycin mobilized a ryanodine receptor (RyR)-independent reticular Ca²⁺ pool and did not affect the excitation-concentration coupling. Second, puromycin pretreatment decreased mitochondrial Ca²⁺ content and slowed down the mitochondrial permeability transition pore (mPTP) opening and the rate of cytosolic Ca²⁺ increase during hypoxia. Finally, this translocon pre-activation also protected cardiomyocytes after in vitro hypoxia reoxygenation and reduced infarct size in mice submitted to in vivo ischemia-reperfusion. Altogether, our report emphasizes the role of translocon in cardioprotection and highlights a new paradigm in cardioprotection by functionally uncoupling the RyR-dependent Ca²⁺ stores and translocon-dependent Ca²⁺ stores.

SUBMITTER: Al-Mawla R

PROVIDER: S-EPMC7290748 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Acute Induction of Translocon-Mediated Ca2+ Leak Protects Cardiomyocytes Against Ischemia/Reperfusion Injury.

Al-Mawla Ribal R Ducrozet Mallory M Tessier Nolwenn N Païta Lucille L Pillot Bruno B Gouriou Yves Y Villedieu Camille C Harhous Zeina Z Paccalet Alexandre A Crola Da Silva Claire C Ovize Michel M Bidaux Gabriel G Ducreux Sylvie S Van Coppenolle Fabien F

Cells 20200525 5

During myocardial infarction, dysregulation of Ca2+ homeostasis between the reticulum, mitochondria, and cytosol occurs in cardiomyocytes and leads to cell death. Ca2+ leak channels are thought to be key regulators of the reticular Ca2+ homeostasis and cell survival. The present study aimed to determine whether a particular reticular Ca2+ leak channel, the translocon, also known as translocation channel, could be a relevant target against ischemia/repe ...[more]

PMID: 32466308

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Project description:Background: Ischemia-reperfusion injury (I/R) strongly affects the prognosis of children with complicated congenital heart diseases (CHDs) who undergo long-term cardiac surgical processes. Recently, the α2-adrenergic receptor agonist Dexmedetomidine (Dex) has been reported to protect cardiomyocytes (CMs) from I/R in cellular models and adult rodent models. However, whether and how Dex may protect human CMs in young children remains largely unknown. Methods and Results: Human ventricular tissue from tetralogy of Fallot (TOF) patients and CMs derived from human-induced pluripotent stem cells (iPSC-CMs) were used to assess whether and how Dex protects human CMs from I/R. The results showed that when pretreated with Dex, the apoptosis marker-TUNEL and cleaved caspase 3 in the ventricular tissue were significantly reduced. In addition, the autophagy marker LC3II was significantly increased compared with that of the control group. When exposed to the hypoxia/reoxygenation process, iPSC-CMs pretreated with Dex also showed reduced TUNEL and cleaved caspase 3 and increased LC3II. When the autophagy inhibitor (3-methyladenine, 3-MA) was applied to the iPSC-CMs, the protective effect of Dex on the CMs was largely blocked. In addition, when the fusion of autophagosomes with lysosomes was blocked by Bafilomycin A1, the degradation of p62 induced by Dex during the autophagy process was suspended. Moreover, when pretreated with Dex, both the human ventricle and the iPSC-CMs expressed more AMP-activated protein kinase (AMPK) and phospho AMPK (pAMPK) during the I/R process. After AMPK knockout or the use of an α2-adrenergic receptor antagonist-yohimbine, the protection of Dex and its enhancement of autophagy were inhibited. Conclusion: Dex protects young human CMs from I/R injury, and α2-adrenergic receptor/AMPK-dependent autophagy plays an important role during this process. Dex may have a therapeutic effect for children with CHD who undergo long-term cardiac surgical processes.

Dataset Information

Acute Induction of Translocon-Mediated Ca²⁺ Leak Protects Cardiomyocytes Against Ischemia/Reperfusion Injury.

Publications

Acute Induction of Translocon-Mediated Ca<sup>2+</sup> Leak Protects Cardiomyocytes Against Ischemia/Reperfusion Injury.

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