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

Abstract

The molecular atlas of postnatal mouse ventricular development has been made available and cardiac regeneration is documented to be a downregulated process. The right ventricle (RV) differs from the left ventricle. How volume overload (VO), a common pathologic state in children with congenital heart disease, affects the downregulated processes of the RV is currently unclear. We created a fistula between the abdominal aorta and inferior vena cava on postnatal day 7 (P7) using a mouse model to induce a prepubertal RV VO. RNAseq analysis of RV (from postnatal day 14 to 21) demonstrated that angiogenesis was the most enriched gene ontology (GO) term in both the sham and VO groups. Regulation of the mitotic cell cycle was the second-most enriched GO term in the VO group but it was not in the list of enriched GO terms in the sham group. In addition, the number of Ki67-positive cardiomyocytes increased approximately 20-fold in the VO group compared to the sham group. The intensity of the vascular endothelial cells also changed dramatically over time in both groups. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the downregulated transcriptome revealed that the peroxisome proliferators-activated receptor (PPAR) signaling pathway was replaced by the cell cycle in the top-20 enriched KEGG terms because of the VO. Angiogenesis was one of the primary downregulated processes in postnatal RV development, and the cell cycle was reactivated under the influence of VO. The mechanism underlying the effects we observed may be associated with the replacement of the PPAR-signaling pathway with the cell-cycle pathway.

Volume Overload Initiates an Immune Response in the Right Ventricle at the Neonatal Stage

“…One sample in the sham group was set as "1"; the other samples referred to the sample. lack of neonatal RV VO models (10,17,18). The current study introduced a neonatal rat RV VO model to study pediatric RV VO, which may narrow down the translational gap from bench to bedside.…”

“…However, the molecular mechanisms initiating and driving RV dysfunction under the influence of VO remains unclear. Systematic reviews have highlighted the translational gap from bench to bedside in terms of RV VO animal models and reveals that there is lack of neonatal RV VO models ( 10 , 17 , 18 ). The current study introduced a neonatal rat RV VO model to study pediatric RV VO, which may narrow down the translational gap from bench to bedside.…”

“…In the adulthood, VO causes fibrosis, hypertrophy, and angiogenesis ( 9 , 10 ); additionally, in the pre-pubetal stage, VO interrupts cardiomyocyte maturation and reactive cell cycle ( 17 , 18 ). Current data show that at the neonatal stage, VO induces immune responses, suggesting that immune responses may be an initiating factor for neonatal cardiac remodeling under the influence of VO and immunosuppressants may be used to prevent neonatal RV remodeling, ultimately leading to RV dysfunction.…”

“…There are two reasons why a neonatal rat VO model is needed when there is a pre-pubetal mouse VO model ( 17 , 18 ). The physiological characteristics of the heart between the pre-pubetal and neonatal period are different.…”

“…At P21, the CMs are fully mature and use oxidative phosphorylation as primary energy source ( 12 , 16 ). Therefore, we previously created a pre-pubertal mouse RV VO model on P7 and demonstrated that the maturation process of RV CMs is partly interrupted by VO, and the underlying mechanism is associated with the replacement of the peroxisome proliferator-activated receptor (PPAR) signaling pathway with the cell-cycle pathway ( 17 , 18 ). These results highlight different responses to VO between pre-pubertal and adult RV, suggesting the importance of developmental stage-specific analysis of the effect of VO on RV remodeling.…”