Increased afterload in PH results in RV dysfunction eventually leading to RV failure and death. To determine significant protein and signaling changes associated with progression of RV dysfunction and transition from compensation to decompensated RV function we performed global proteomic analysis of multiple preclinical rat models of PH with different times and severity of RV dysfunction. Four and 7-week (wk) Sugen/Hypoxia treatment (SUH) in the Sprague Dawley strain initiates mild (4-wk SUH) and more severe (7-wk SUH) RV dysfunction. Four-wk SUH Fisher (4-wk CDF) rats exhibit greater RV dysfunction. Pulmonary artery banding for 7 wk (7-wk PAB). N = 6 animals/group (3M/3F). RV proteomes were analyzed by DIA-MS and enrichment was performed using IPA software. In the mild RV dysfunction 4-wk SUH animals, there were 210 and 159 significantly (B-H adj p < 0.05) up and downregulated proteins vs. control. Generally, greater quantity and magnitude of changes were observed in the more severe 7-wk SUH (543 up/653 down), and 7-wk PAB models (512 up/504 down) with the most drastic changes in the 4-wk CDF (1062 up/952 down). Highest common negatively enriched pathways included fatty acid oxidation, various amino acid degradation and catabolism pathways, peroxisomal protein import, and mitochondrial protein degradation. Highest common positively enriched pathways included mitochondrial dysfunction, and nuclear cytoskeleton, IL-13, 14 and IGF signaling and pulmonary fibrosis. Differentially enriched cascades between groups suggest less inflammation and improved mitochondrial function in the 7-wk SUH vs. 4-wk CDF. Similar differences were found between 7wk PAB and 4wk CDF. Proteomics analysis of dysfunctional RV in rat models of PH reveals numerous mitochondrial and metabolic changes associated with RV dysfunction and more expansive mitochondrial and inflammatory proteome derangements with more severe RV dysfunction.
Ma et al. (Sun,) studied this question.