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Pressure overload greatly promotes neonatal right ventricular cardiomyocyte proliferation - a new model for heart regeneration study

ABSTRACT: Background: Current mammalian model for heart regeneration research is limited in apex amputation or myocardium infarction, both of which are controversy. Moreover, RNAseq demonstrated there were a very limited set of differential expressed genes between sham and operation heart in the myocardium infarction model. Here we investigated whether pressure overload in the right ventricle(RV), a common phenomenon in congenital heart disease children, could be a better animal model for heart regeneration study when consider cardiomyocyte(CM) proliferation as the most important index. Methods and results: Pressure overload was induced by pulmonary artery banding (PAB) on day1 and confirmed by echocardiography and hemodynamic measurements at postnatal day 7(P7). RNAseq analyses of purified RVCM at P7 from PAB and sham-operated rats revealed there were 5469 differential expressed genes between these two groups. GO and KEGG analysis showed that these genes mainly mediated mitosis and cell division. Cell proliferation assay indicates a continuous over-proliferation of RVCM after PAB, in particular for P3. In addition, there were ~2 times-fold increase of Ki67/Phh3 -positive CM in human overload RV compared to non-overload RV. Other features about this model included CM hypotrophy and no fibrosis.. Conclusions: Pressure overload profoundly promotes RVCM proliferation in the neonatal stage both in rats and human beings, activated a regeneration-specific gene program, and may offer a better alternative animal model for heart regeneration research..

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE139561 | GEO | 2020/08/19

REPOSITORIES: GEO

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Project description:Background: Right ventricular (RV) and left ventricular (LV) myocardium differ in their response to pressure-overload hypertrophy (POH). In this report we use microarray and proteomic analyses to identify pathways modulated by LV-, and RV-POH in the immature heart. Methods: Newborn New Zealand White rabbits underwent banding of the descending thoracic aorta (LV-POH; n=6). RV-POH was achieved by banding the pulmonary artery (n=6). Sham–control animals (SC; n=6 each) were sham-manipulated. Following 4 (LV-POH) and 6 weeks (RV-POH) recovery, the hearts were removed and matched sample RNA and proteins were isolated for microarray and proteomic analysis. Results: There was no difference in body weight in RV-, LV-POH vs. SC but there was a significant increase vs. SC in RV (3.2±0.8g vs. 1.2±0.3g; P<0.01) and LV weight (7.08±0.6g vs. 4.02±0.2g; P<0.01). Fractional area change (RV-POH) and shortening fraction (LV-POH) decreased significantly (23±6 vs. 47±6 and 21±4 vs.44±2, respectively, P<0.01). Microarray analysis demonstrated that LV-POH enriched pathways for oxidative phosphorylation, mitochondria energy pathways, actin, ILK, hypoxia, calcium and protein kinase-A signalling. RV-POH enriched pathways for cardiac oxidative phosphorylation. Proteomic analysis revealed 19 proteins were uniquely expressed in LV-POH vs. SC. Functional annotation clustering analysis indicated significant enrichment for the mitochondrion, cellular macromolecular complex assembly and oxidative phosphorylation. RV-POH had 15 uniquely expressed proteins vs. SC. Functional annotation clustering analysis indicated significant enrichment in structural constituents of muscle, cardiac muscle tissue development and calcium handling. Conclusion: Our results identify unique transcript and protein expression profiles in LV, RV-POH and provide new insight into the biological basis of ventricular specific hypertrophy. 3 different conditions: PAB-RV vs. Sham-control RV, PAB-RV [test] vs. PAB-LV [control], AOB-LV vs. Sham-control LV.

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Pressure overload greatly promotes neonatal right ventricular cardiomyocyte proliferation - a new model for heart regeneration study

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