Pressure Overload Greatly Promotes Neonatal Right Ventricular Cardiomyocyte Proliferation: A New Model for the Study of Heart Regeneration

Abstract

Background Current mammalian models for heart regeneration research are limited to neonatal apex amputation and myocardial infarction, both of which are controversial. RNA seq 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 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/ pHH 3/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. 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.

A Neonatal Mouse Model for Pressure Overload: Myocardial Response Corresponds to Severity

“…Gradually, pressure overload on neonates has gained the attention of researchers. Ye et al (25) performed an RNAseq analysis on cardiomyocytes from the right ventricle of neonatal mice with pulmonary artery banding and reported differential expression of genes that mainly mediated mitosis and cell division. Consistent with their point of view, the present study also considered that pressure overload in neonates was better than apex resection and MI models to study cardiomyocyte proliferation.…”

Progress in cardiac research: from rebooting cardiac regeneration to a complete cell atlas of the heart

“… 25 , 26 Against this background, Ye et al . 27 recently showed in the rat, that pulmonary artery banding at post-natal day 1 induces right ventricle pressure overload. This triggers myocardial renewal activation by over-proliferation of resident neonatal cardiomyocytes.…”

Downregulated developmental processes in the postnatal right ventricle under the influence of a volume overload

“…Promoting the proliferation of endogenous cardiomyocytes is an important research direction for heart regeneration and an important means of treating heart failure [1][2][3][4]. Both neonatal mouse and human cardiomyocytes possess strong proliferative potential but with increasing age, the proliferative potential of cardiomyocytes gradually disappears, and by adulthood, the proliferative capability is negligible [5][6][7][8]. To determine the molecular mechanisms that mediate postnatal loss of cardiomyocyte proliferation, Virpi et al combined transcriptomics with proteomic and metabolomic analyses in the early postnatal mouse heart (from postnatal day 1[P1] to P23) [9].…”

“…More importantly, the left and right ventricles react differently when facing the same stimulus. For example, in the face of pressure overload, the proliferation of neonatal cardiomyocytes in the RV is more profound than in the left ventricle [5,14]. In addition, the treatment and prognosis of many children with congenital heart disease are determined by the functions of the RV as pertaining to left ventricular dysplasia or transposition of the great arteries, for example [15,16].…”