Postnatal Right Ventricular Developmental Track Changed by Volume Overload

Abstract

Background Current right ventricular (RV) volume overload (VO) is established in adult mice. There are no neonatal mouse VO models and how VO affects postnatal RV development is largely unknown. Methods and Results Neonatal VO was induced by the fistula between abdominal aorta and inferior vena cava on postnatal day 7 and confirmed by abdominal ultrasound, echocardiography, and hematoxylin and eosin staining. The RNA‐sequencing results showed that the top 5 most enriched gene ontology terms in normal RV development were energy derivation by oxidation of organic compounds, generation of precursor metabolites and energy, cellular respiration, striated muscle tissue development, and muscle organ development. Under the influence of VO, the top 5 most enriched gene ontology terms were angiogenesis, regulation of cytoskeleton organization, regulation of vasculature development, regulation of mitotic cell cycle, and regulation of the actin filament‐based process. The top 3 enriched signaling pathways for the normal RV development were PPAR signaling pathway, citrate cycle (Tricarboxylic acid cycle), and fatty acid degradation. VO changed the signaling pathways to focal adhesion, the PI3K‐Akt signaling pathway, and pathways in cancer. The RNA sequencing results were confirmed by the examination of the markers of metabolic and cardiac muscle maturation and the markers of cell cycle and angiogenesis. Conclusions A neonatal mouse VO model was successfully established, and the main processes of postnatal RV development were metabolic and cardiac muscle maturation, and VO changed that to angiogenesis and cell cycle regulation.

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.…”