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.

中文翻译：

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全基因组翻译重编程的基因对超负荷诱导的心力衰竭中的心肌细胞功能很重要。

心力衰竭发展过程中基因翻译效率的全基因组变化知之甚少。我们测试了这一假设，即心脏基因翻译效率的异常变化与对持续性应激刺激的心肌细胞代偿失调的发展有关。我们证明了小鼠中的慢性压力超负荷导致全基因组翻译效率的重新编程，其中> 50％的翻译组在从心肌补偿到代偿失调的过渡过程中表现出降低的翻译效率。重要的是，这些翻译受阻的基因包括那些参与血管生成和能量代谢的基因。而且，我们发现应激诱导的翻译重编程伴随着真核生物起始因子2α（eIF2α）介导的应激反应途径的持续激活。通过心脏特异性过表达eIF2α-S51A突变体来抵消内源性eIF2α功能，可改善心肌失代偿的发展，同时改善心脏功能基因的翻译并增加血管生成反应。这些数据表明，具有基本功能的心脏基因的转录和翻译之间的不匹配可能代表了一种新的分子机制，该机制是响应慢性应激刺激而发生心肌失代偿的基础，而eIF2α途径可能是恢复最佳状态的可行治疗靶点。抑制的心脏基因的翻译。