1. Pharmacological preconditioning protects from ischemia/reperfusion-induced apoptosis by modulating Bcl-xL expression through a ROS-dependent mechanism
- Author
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Johanna Chiche, Jean-Ehrland Ricci, Romain M. Rozier, Blandine Madji Hounoum, Elodie Villa, Rachel Paul, Els Verhoeyen, Sandrine Marchetti, Ashaina Vandenberghe, Rana Mhaidly, Michel Carles, and Marc Raucoules
- Subjects
0301 basic medicine ,Programmed cell death ,Cell Survival ,Ischemia ,bcl-X Protein ,Bcl-xL ,Apoptosis ,Myocardial Reperfusion Injury ,Pharmacology ,Biochemistry ,03 medical and health sciences ,Sevoflurane ,0302 clinical medicine ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Myocytes, Cardiac ,Induced pluripotent stem cell ,Molecular Biology ,Protein kinase B ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,Cell Biology ,medicine.disease ,Metformin ,Rats ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Reperfusion Injury ,biology.protein ,Signal transduction ,Reactive Oxygen Species ,Signal Transduction - Abstract
Myocardial ischemia/reperfusion (I/R) injury is a frequent perioperative threat, with numerous strategies developed to limit and/or prevent it. One interesting axis of research is the anesthetic preconditioning (APc) agent's hypothesis (such as sevoflurane, SEV). However, APc's mode of action is still poorly understood and volatile anesthetics used as preconditioning agents are often not well suited in clinical practice. Here, in vitro using H9C2 cells lines (in myeloblast state or differentiated toward cardiomyocytes) and in vivo in mice, we identified that SEV-induced APc is mediated by a mild induction of reactive oxygen species (ROS) that activates Akt and induces the expression of the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL), therefore protecting cardiomyocytes from I/R-induced death. Furthermore, we extended these results to human cardiomyocytes (derived from induced pluripotent stem - IPS - cells). Importantly, we demonstrated that this protective signaling pathway induced by SEV could be stimulated using the antidiabetic agent metformin (MET), suggesting the preconditioning properties of MET. Altogether, our study identified a signaling pathway allowing APc of cardiac injuries as well as a rational for the use of MET as a pharmacological preconditioning agent to prevent I/R injuries.
- Published
- 2020