Transcriptomic Analysis of the Right and Left Ventricle in Normoxia and Hypoxia (a Model of Pulmonary Arterial Hypertension)

Abstract

The pathobiology of pulmonary arterial hypertension (PAH) involves the remodeling of the pulmonary artery within the lung characterized by vasoconstriction, hypertrophy, fibrosis and thrombosis. These factors lead to increased pulmonary vascular resistance (PVR), which, in turn, can produce progressive remodeling of the right ventricle (RV) and eventual right heart failure. Current therapy for PAH emphasizes approaches that decrease PVR, but does not work for some patients and does not specifically target the RV. This study tested the hypothesis that the RV contains a unique subset of genes expressed during remodeling that may serve as a platform to identify and develop novel treatment strategies. To test this hypothesis, we subjected Sprague Dawley rats to hypoxia (10% O2, H‐rats) for two weeks, or to normoxia (N‐rats) as a control (n=3–4/treatment). H‐rats had a significant, 2.19‐fold increase in the Fulton Index (right/[left + septum] ventricular weight): 0.458 ± 0.036 (H‐rats), 0.210 ± 0.020 (N‐rats); mean ± standard deviation, Student's t‐test p<0.0001), indicating significant RV remodeling. To examine mRNA expression, we utilized RNA sequencing (RNA‐seq) of the RV and the left ventricle (LV). Using differential expression analysis, we identified 2,430 genes with significantly (False discovery rate [FDR] <0.1 using multiple testing) altered expression in the RV of H‐rats vs. N‐rats and 504 genes with significantly altered expression in the LV between the two groups of rats. Differentially expressed genes in the RV of H‐rats vs. N‐rats included GPCRs and other widely used drug targets. In normoxia, the RV and LV differentially expressed 299 genes compared to 423 genes under hypoxic conditions. These results indicate that: 1) a subset of genes are differentially expressed in the RV compared to the LV and 2) a large change in the transcriptome occurs with hypoxia‐induced RV remodeling. These findings raise the possibility that treatments for PAH might be directed at gene products selectively expressed in RV remodeling and be able to spare the LV, thus providing a novel approach for treating a currently unmet need for patients with RV hypertrophy and failure.Support or Funding InformationSupported by Department of Defense (W81XWH‐14‐1‐0372) and the National Institutes of Health (5T32HL007444‐33)