Abstract Body (Do not enter title and authors here): Background: Right ventricular dysfunction (RVD) is the leading cause of mortality in pulmonary arterial hypertension, but there are no available RV specific therapies. At present, the cellular and molecular mediators of progressive RVD are poorly defined.
Methods: Control and pulmonary artery banded (PAB) pigs underwent comprehensive cardiac MRI examination, hemodynamic study, and histological evaluation. PAB pigs were separated into two groups: mild RVD: (RVEF: 34-46%) and severe RVD (RVEF<25%). Single-nucleus-RNA sequencing delineated cell-type specific changes between groups. Quantitative proteomics examined alterations in mitochondrial and cytosolic protein abundances. Phosphoproteomics identified dysregulated RV kinases.
Results: Single-nucleus-RNA sequencing demonstrated severe RVD resulted in decreased abundance of cardiomyocytes, and elevated macrophages and lymphocytes, which was not as pronounced in mild RVD. Integration of snRNAseq and proteomics showed a progressive loss of complex metabolism with worsening RV function with downregulation of fatty acid and oxidative phosphorylation transcripts/proteins. Proteostasis evaluation (ribosomes, chaperones, proteasome) of both the cytoplasmic and mitochondrial fractions revealed an impaired mitochondrial proteostasis signature but preserved cytoplasmic proteostasis with the exception of increased cytoplasmic ribosomes. Finally, kinome mapping of differentially regulated phosphoproteins nominated GSK3b, LBK1, MARK1, and LATS2 as kinases was heightened activity only in the severe RVD group.
Conclusion: Progressive RVD is defined by heightened RV inflammation, suppressed cardiomyocyte metabolism, impaired mitochondrial proteostasis, and a distinct kinome map for therapeutic targeting. These data provide a comprehensive, multi-omic map of RVD and delineate novel targets to augment RV function.