A New Model For The Study Of Heart Regeneration
Shanghai Children's Medical Center, Shanghai, China.
BACKGROUND: Current 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 RESULTS: In the rat model, pressure overload was induced by pulmonary artery banding (PAB) on postnatal day 1 and confirmed by echocardiography and hemodynamic measurements at postnatal day 7. RNAseq analyses of purified right ventricular cardiomyocytes at postnatal day 7 from PAB and sham-operated rats revealed that there were 5469 differentially expressed genes between these two groups. GO and KEGG analysis showed that these genes mainly mediated mitosis and cell division. Cell proliferation assays indicated a continuous over-proliferation of cardiomyocytes in the right ventricle after PAB, in particular for the first three postnatal days. We also validated the model using samples from overloaded right ventricles of human patients. There was an approximately two-fold increase of Ki67/pHH3/aurora B-positive cardiomyocytes in human-overloaded right ventricles compared to non-overloaded right ventricles. Other features of this animal model included cardiomyocyte hypotrophy with no fibrosis.
CONCLUSIONS:Pressure 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.
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