An integrated proteomic and transcriptomic signature of the failing right ventricle in monocrotaline induced pulmonary arterial hypertension in male rats

Abstract

Aim: Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy that results in death from right ventricular failure (RVF). There is limited understanding of the molecular mechanisms of RVF in PAH.Methods: In a PAH-RVF model induced by injection of adult male rats with monocrotaline (MCT; 60 mg/kg), we performed mass spectrometry to identify proteins that change in the RV as a consequence of PAH induced RVF. Bioinformatic analysis was used to integrate our previously published RNA sequencing data from an independent cohort of PAH rats.Results: We identified 1,277 differentially regulated proteins in the RV of MCT rats compared to controls. Integration of MCT RV transcriptome and proteome data sets identified 410 targets that are concordantly regulated at the mRNA and protein levels. Functional analysis of these data revealed enriched functions, including mitochondrial metabolism, cellular respiration, and purine metabolism. We also prioritized 15 highly enriched protein:transcript pairs and confirmed their biological plausibility as contributors to RVF. We demonstrated an overlap of these differentially expressed pairs with data published by independent investigators using multiple PAH models, including the male SU5416-hypoxia model and several male rat strains.Conclusion: Multiomic integration provides a novel view of the molecular phenotype of RVF in PAH which includes dysregulation of pathways involving purine metabolism, mitochondrial function, inflammation, and fibrosis.

Characterizing the Spatiotemporal Transcriptomic Response of the Right Ventricle to Acute Pressure Overload

“…In 2021, Park et al [10] reported that the end-stage transcriptomic signatures between SuHx and MCT rats were moderately similar (2693 common genes; 34% of the differentially expressed MCT genes; 86% of the differentially expressed SuHx genes). The genes they identified as being important in RV remodeling were in broad agreement with previous RV gene-expression studies of both MCT [27,28] and SuHx [29] rats, and most of the genes found for MCT rats have also been reported as differentially expressed at the protein level [27].…”

A Multi-omic and Multi-Species Analysis of Right Ventricular Failure

“…Because Fatty Acid Oxidation (FAO) and ETC pathways were identified in our porcine analysis and alterations in these pathways are present in human heart failure(23,24), we evaluated and compared the relative changes in FAO and ETC in rodents (GSE119754, PXD027273), pigs, and humans (GSE198618) (10,11,25). In the proteomics analysis, abundances of nearly all FAO and ETC proteins were reduced in MCT rats as compared to control rats ( Figure 6A-B ).…”

Proteomic and Phosphoproteomic Analysis of Right Ventricular Hypertrophy in the Pulmonary Hypertension Rat Model

“…As we can see, proteins involved in the same pathway tend to form a tight interaction with each other. Recent proteomic analysis on the RV from MCT-induced PAH model rats was reported by three groups, Hołda et al, 8 Qin et al, 7 and Hindmarch et al 22 Several upregulated proteins were identified in our study, including Postn, Nppa, Hmox1 (heme oxygenase 1), Plod2 (procollagen-lysine 5-dioxygenase), and Gpnmb (glycoprotein nmb), also noted by Hindmarch et al In addition to these five proteins, the upregulation of several other hypertrophy or heart failure-associated proteins was further validated using qRT-PCR, including Fstl1, Ltbp2, and Ncam1. This consistency underscores the reliability of our proteomic analysis.…”