Genome-wide changes in gene translational efficiency during the development of heart failure are poorly understood. We tested the hypothesis that aberrant changes in translational efficiency of cardiac genes are associated with the development of myocyte decompensation in response to persistent stress stimuli. We demonstrated that chronic pressure overload in mice resulted in a genome-wide reprogramming of translational efficiency, with >50% of the translatome exhibiting decreased translational efficiencies during the transition from myocardial compensation to decompensation. Importantly, these translationally repressed genes included those involved in angiogenesis and energy metabolism. Moreover, we showed that the stress-induced translational reprogramming was accompanied by persistent activation of the eukaryotic initiation factor 2α (eIF2α)-mediated stress response pathway. Counteracting the endogenous eIF2α functions by cardiac-specific overexpression of an eIF2α-S51A mutant ameliorated the development of myocyte decompensation, with concomitant improvements in translation of cardiac functional genes and increases in angiogenic responses. These data suggest that the mismatch between transcription and translation of the cardiac genes with essential functions may represent a novel molecular mechanism underlying the development of myocyte decompensation in response to chronic stress stimuli, and the eIF2α pathway may be a viable therapeutic target for recovering the optimal translation of the repressed cardiac genes.
Keywords: Angiogenesis; Cellular stress; Heart failure; Protein translation; Ribosome profiling; Systems biology.
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