BackgroundCurrent mammalian models for heart regeneration research are limited to neonatal apex amputation and myocardial infarction, both of which are controversial. RNAseq has demonstrated a very limited set of differentially expressed genes between sham and operated hearts in myocardial infarction models. Here, we investigated in rats whether pressure overload in the right ventricle, a common phenomenon in children with congenital heart disease, could be used as a better animal model for heart regeneration studies when considering cardiomyocyte proliferation as the most important index.Methods and ResultsIn the rat model, pressure overload was induced by pulmonary artery banding on postnatal day 1 and confirmed by echocardiography and hemodynamic measurements at postnatal day 7. RNA sequencing analyses of purified right ventricular cardiomyocytes at postnatal day 7 from pulmonary artery banding and sham‐operated rats revealed that there were 5469 differentially expressed genes between these 2 groups. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that these genes mainly mediated mitosis and cell division. Cell proliferation assays indicated a continuous overproliferation of cardiomyocytes in the right ventricle after pulmonary artery banding, in particular for the first 3 postnatal days. We also validated the model using samples from overloaded right ventricles of human patients. There was an approximately 2‐fold increase of Ki67/pHH3/aurora B‐positive cardiomyocytes in human‐overloaded right ventricles compared with nonoverloaded right ventricles. Other features of this animal model included cardiomyocyte hypotrophy with no fibrosis.ConclusionsPressure overload profoundly promotes cardiomyocyte proliferation in the neonatal stage in both rats and human beings. This activates a regeneration‐specific gene program and may offer an alternative animal model for heart regeneration research.

中文翻译：

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压力超负荷极大地促进了新生儿右心室心肌细胞的增殖：一种用于心脏再生研究的新模型。

背景技术当前用于心脏再生研究的哺乳动物模型仅限于新生儿根尖切除术和心肌梗塞，这两者都存在争议。 核糖核酸seq已证明在心肌梗死模型中假手术和手术心脏之间差异表达的基因非常有限。在这里，我们以大鼠心肌细胞增殖为最重要的指标，研究了在先天性心脏病患儿中常见的右心室压力超负荷是否可以用作心脏再生研究的更好动物模型。在大鼠模型中，出生后第1天通过肺动脉束带诱发压力超负荷，并在出生后第7天通过超声心动图和血流动力学测量结果证实。核糖核酸肺动脉束缚和假手术大鼠在出生后第7天纯化的右心室心肌细胞的测序分析表明，这两组之间有5469个差异表达的基因。基因本体论和《京都基因与基因组百科全书》的分析表明，这些基因主要介导有丝分裂和细胞分裂。细胞增殖试验表明，在肺动脉束缚后，特别是在出生后的前三天，右心室中的心肌细胞持续过度增殖。我们还使用人类患者超负荷的右心室样本验证了该模型。Ki67 /大约增加了2倍酸碱度与未超负荷的右心室相比，人超负荷的右心室中的3 / a极光B阳性心肌细胞。该动物模型的其他特征包括没有纤维化的心肌细胞萎缩。结论压力超负荷可在大鼠和人类的新生阶段显着促进心肌细胞的增殖。这将激活再生特异性基因程序，并可能为心脏再生研究提供替代的动物模型。