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 H2O2 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 H2O2 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 H2O2 promoted mTOR phosphorylation, associated with differential recruitment of some mRNAs to the polysomes for translation. Some of the upregulated genes induced by low H2O2 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.
Highlights
Heart failure, the end result of various progressive heart diseases, is the leading cause of cardiovascular mortality in the developing world [1]
To explore this relationship in the context of redox stress induced signalling, we examined the effects of H2O2 on intracellular ATP concentrations in neonatal rat ventricular myocytes (Fig. 1A)
Though not completely representative of an adult cardiomyocyte, they are an appropriate model for assessment of general concepts of intracellular signalling in terminally-differentiated cardiomyocytes
Summary
The end result of various progressive heart diseases, is the leading cause of cardiovascular mortality in the developing world [1]. The consequent inability of the heart to pump blood to the body is associated with loss of terminally-differentiated contractile cardiomyocytes, whether by necrosis (as occurs following myocardial infarction) or, if energy levels suffice, one of several forms of programmed cell death including apoptosis [2,3,4]. High levels of reactive oxygen species (ROS) are clearly damaging and result in unregulated cell death. More moderate levels induce apoptosis through the mitochondrial death pathway with cleavage and activation of caspases 9 and 3, and regulated dismantling of cellular contents. Low ROS levels are associated with cardiomyocyte survival and may even promote hypertrophy. These are examples of Abbreviations: AMPK, AMP-activated protein kinase; AS, antisense; FDR, false discovery rate; IEG, immediate early gene; mTOR, mammalian target of rapamycin; mTORC, mTOR complex; ODN, oligodeoxynucleotide; ROS, reactive oxygen species
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