Meijles, DN; Zoumpoulidou, G; Markou, T; Rostron, KA; Patel, R; Lay, K; Handa, BS; ... Clerk, A; + view all Meijles, DN; Zoumpoulidou, G; Markou, T; Rostron, KA; Patel, R; Lay, K; Handa, BS; Wong, B; Sugden, PH; Clerk, A; - view fewer (2019) The cardiomyocyte “redox rheostat”: Redox signalling via the AMPK-mTOR axis and regulation of gene and protein expression balancing survival and death. Journal of Molecular and Cellular Cardiology , 129 pp. 118-129. 10.1016/j.yjmcc.2019.02.006.

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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}O_{2} 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 H_{2}O_{2} 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 H_{2}O_{2} promoted mTOR phosphorylation, associated with differential recruitment of some mRNAs to the polysomes for translation. Some of the upregulated genes induced by low H_{2}O_{2} levels are cytoprotective. We identified p21^{Cip1/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.

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