1. The cardiomyocyte "redox rheostat": Redox signalling via the AMPK-mTOR axis and regulation of gene and protein expression balancing survival and death.
- Author
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Meijles DN, Zoumpoulidou G, Markou T, Rostron KA, Patel R, Lay K, Handa BS, Wong B, Sugden PH, and Clerk A
- Subjects
- Adenosine Triphosphate metabolism, Animals, Animals, Newborn, Cell Survival drug effects, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Cytoprotection drug effects, Doxorubicin pharmacology, Enzyme Activation drug effects, Genes, Immediate-Early, Hydrogen Peroxide metabolism, Mechanistic Target of Rapamycin Complex 1 metabolism, Myocytes, Cardiac drug effects, Oxidation-Reduction, Phosphorylation drug effects, Polyribosomes metabolism, Protein Biosynthesis drug effects, Proto-Oncogene Proteins c-akt metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Sprague-Dawley, Stress, Physiological drug effects, AMP-Activated Protein Kinases metabolism, Apoptosis drug effects, Gene Expression Regulation, Myocytes, Cardiac cytology, Myocytes, Cardiac metabolism, Signal Transduction drug effects, TOR Serine-Threonine Kinases metabolism
- Abstract
Reactive oxygen species (ROS) play a key role in development of heart failure but, at a cellular level, their effects range from cytoprotection to induction of cell death. Understanding how this is regulated is crucial to develop novel strategies to ameliorate only the detrimental effects. Here, we revisited the fundamental hypothesis that the level of ROS per se is a key factor in the cellular response by applying different concentrations of H
2 O2 to cardiomyocytes. High concentrations rapidly reduced intracellular ATP and inhibited protein synthesis. This was associated with activation of AMPK which phosphorylated and inhibited Raptor, a crucial component of mTOR complex-1 that regulates protein synthesis. Inhibition of protein synthesis by high concentrations of H2 O2 prevents synthesis of immediate early gene products required for downstream gene expression, and such mRNAs (many encoding proteins required to deal with oxidant stress) were only induced by lower concentrations. Lower concentrations of H2 O2 promoted mTOR phosphorylation, associated with differential recruitment of some mRNAs to the polysomes for translation. Some of the upregulated genes induced by low H2 O2 levels are cytoprotective. We identified p21Cip1/WAF1 as one such protein, and preventing its upregulation enhanced the rate of cardiomyocyte apoptosis. The data support the concept of a "redox rheostat" in which different degrees of ROS influence cell energetics and intracellular signalling pathways to regulate mRNA and protein expression. This sliding scale determines cell fate, modulating survival vs death., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2019
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