Dataset Information

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. 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 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. 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.

SUBMITTER: Ye L

PROVIDER: S-EPMC7429015 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Ye Lincai L Wang Shoubao S Xiao Yingying Y Jiang Chuan C Huang Yanhui Y Chen Huiwen H Zhang Haibo H Zhang Hao H Liu Jinfen J Xu Zhuoming Z Hong Haifa H

Journal of the American Heart Association 20200530 11

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 hea ...[more]

PMID: 32475201

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Project description:Myeloid-derived growth factor (Mydgf), a paracrine protein secreted by bone marrow-derived monocytes and macrophages, was found to protect against cardiac injury following myocardial infarction (MI) in adult mice. We speculated that Mydgf might improve heart function via myocardial regeneration, which is essential for discovering the target to reverse heart failure. Methods: Two genetic mouse lines were used: global Mydgf knockout (Mydgf-KO) and Mydgf-EGFP mice. Two models of cardiac injury, apical resection was performed in neonatal and MI was performed in adult mice. Quantitative reverse transcription-polymerase chain reaction, western blot and flow cytometry were performed to study the protein expression. Immunofluorescence was performed to detect the proliferation of cardiomyocytes. Heart regeneration and cardiac function were evaluated by Masson's staining and echocardiography, respectively. RNA sequencing was employed to identify the key involved in Mydgf-induced cardiomyocyte proliferation. Mydgf recombinant protein injection was performed as a therapy for cardiac repair post MI in adult mice. Results: Mydgf expression could be significantly induced in neonatal mouse hearts after cardiac injury. Unexpectedly, we found that Mydgf was predominantly expressed by endothelial cells rather than macrophages in injured neonatal hearts. Mydgf deficiency impeded neonatal heart regeneration and injury-induced cardiomyocyte proliferation. Mydgf recombinant protein promoted primary mouse cardiomyocyte proliferation. Employing RNA sequencing and functional verification, we demonstrated that c-Myc/FoxM1 pathway mediated Mydgf-induced cardiomyocyte expansion. Mydgf recombinant protein improved cardiac function in adult mice after MI injury with inducing cardiomyocyte proliferation. Conclusion: Mydgf promotes cardiomyocyte proliferation by activating c-Myc/FoxM1 pathway and improves heart regeneration both in neonatal and adult mice after cardiac injury, providing a potential target to reverse cardiac remodeling and heart failure.

Project description:Backgound: Cardiac pressure overload, for example in patients with aortic stenosis, induces irreversible damage in the myocardium leading to cardiac dysfunction, cardiomyocyte hypertrophy and interstitial fibrosis. We therefore hypothesized that insufficient cardiac regeneration might contribute to the progression of pressure overload dependent disease. Here, we aimed to elucidate whether pressure overload in the regenerative stage shortly after birth could lead to a more adaptive cardiac response than in the non-regenerative stage in mice.nTAC in the non-regenerative stage induced cardiac dysfunction, myocardial fibrosis and cardiomyocyte hypertrophy. In contrast, during induction of nTAC in the regenerative stage, cardiac function remained intact and this was associated with enhanced myocardial angiogenesis and innervation as well as increased cardiomyocyte proliferation, but neither hypertrophy nor fibrosis. Mechanistically, inhibition of cardiomyocyte proliferation and angiogenesis in nTAC in the regenerative phase by rapamycin triggered mortality and myocardial fibrosis, which both also similarly occurred upon inhibition of angiogenesis by PTK787, suggesting that both processes are essential for the adaptive cardiac response to nTAC. A comparative genome-wide transcriptomic analysis between hearts after nTAC in the regenerative versus the non-regenerative stage defined differentially expressed functional gene classes, and a related bioinformatics analysis suggested the transcription factor GATA4 as master regulator of the regenerative gene-program. Indeed, cardiomyocyte specific deletion of GATA4 converted the regenerative nTAC into a non-regenerative, maladaptive response.tablished a new model of neonatal pressure-overload in mice, which when applied in the regenerative postnatal stage, triggers a purely adaptive myocardial response. Employing this model to identify new regulators might lead to novel therapeutic strategies to combat pressure overload induced myocardial disease.

Dataset Information

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

Publications

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

Similar Datasets

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