714 - Increased Protein Synthesis and Metabolic Adaptation Are Associated With Adaptive Right Ventricular Remodeling In Congenital Heart Disease-Associated Pulmonary Hypertension
Monday, May 1, 2023
9:30 AM – 11:30 AM ET
Poster Number: 714 Publication Number: 714.4
Michael Smith, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Samuel Chiacchia, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Sanjeev Ashok. Datar, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Jason Boehme, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Eleana S. Guardado, Stanford, Palo Alto, CA, United States; Vinicio A.. De Jesus Perez, Stanford University, Stanford, CA, United States; Jeffrey Fineman, UCSF Benioff Children's Hospital San Francisco, San Francisco, CA, United States
Fellow University of California, San Francisco, School of Medicine University of California San Francisco San Francisco, California, United States
Background: Right ventricular (RV) performance is the strongest predictor of morbidity and mortality in pulmonary hypertension (PH). Children with PH secondary to congenital heart disease (CHD) undergo an adaptive remodeling of the RV that preserves RV function as opposed to the maladaptation that leads to RV wall stress, dilation and failure in other forms of PH. The mechanism of this adaptation is unknown. In an ovine model of CHD-associated PH, we mimicked adaptive RV remodeling and demonstrated a capacity to intrinsically increase contractility and efficiently maintain RV output in response to acute RV afterload. Elucidating the mechanisms of this remodeling may identify therapeutic targets for supporting RV function. Objective: To characterize the RNA expression profile and identify key biological pathways that are differentially regulated in a model of CHD-PH with adaptive RV performance. Design/Methods: An ovine model of CHD-PH was prepared via surgical implantation of an aortopulmonary graft in the late gestation fetus to mimic a chronic left-to-right cardiac shunt. Four weeks after spontaneous delivery, lambs were anesthetized for invasive hemodynamic measurements and tissue harvest. Bulk RNA sequencing was performed on RV free wall tissue from 4 shunt lambs and 3 controls. RNA reads were mapped to the sheep genome Ovis Aries (Ovar v3.1). Differential gene expression employing the exact test method, gene ontology and pathway enrichment analyses were performed. Results: Hierarchical clustering of shunt versus control lambs revealed 412 differentially expressed genes at a false discovery rate < 0.05 and fold change >2, 232 up- and 180 downregulated in shunt lambs (Figure 1). Gene ontology demonstrated upregulation of biological processes related to protein synthesis and downregulation of processes related to protein catabolism and fatty acid oxidation in shunt lambs (Figure 2). Pathway analysis highlighted alterations in pathways specifically involved in metabolic adaptation and in signaling involving EIF2, WNT/Ca and ERK/MAPK, which play key roles in protein synthesis, cell proliferation and growth factor signaling.
Conclusion(s): The transcriptome of the adaptive shunt RV reveals a profile favoring protein synthesis over amino acid catabolism. This occurs in the context of a shift in cellular metabolism away from fatty acid oxidation, an established process in the progression to RV failure. These findings suggest that protein biosynthesis and growth factor signaling may play key roles in mitigating the detrimental effects of the metabolic transition that contributes to cardiomyocyte dysfunction in RV failure. Heatmap_PAS_Colored.jpeg
