Abstract
Pulmonary arterial hypertension (PAH) is a severe and progressive disease that affects the heart and lungs and a global health concern that impacts individuals and society. Studies have reported that some proteins related to mitochondrial metabolic functions could play an essential role in the pathogenesis of PAH, and their specific expression and biological function are still unclear. We successfully constructed a monocrotaline- (MCT-) induced PAH rat model in the present research. Then, the label-free quantification proteomic technique was used to determine mitochondrial proteins between the PAH group (n = 6) and the normal group (n = 6). Besides, we identified 1346 mitochondrial differentially expressed proteins (DEPs) between these two groups. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the mainly mitochondrial DEPs' biological functions and the signal pathways. Based on the protein-protein interaction (PPI) network construction and functional enrichment, we screened 19 upregulated mitochondrial genes (Psmd1, Psmc4, Psmd13, Psmc2, etc.) and 123 downregulated mitochondrial genes (Uqcrfs1, Uqcrc1, Atp5c1, Atp5a1, Uqcrc2, etc.) in rats with PAH. Furthermore, in an independent cohort dataset and experiments with rat lung tissue using qPCR, validation results consistently showed that 6 upregulated mitochondrial genes (Psmd2, Psmc4, Psmc3, Psmc5, Psmd13, and Psmc2) and 3 downregulated mitochondrial genes (Lipe, Cat, and Prkce) were significantly differentially expressed in the lung tissue of PAH rats. Using the RNAInter database, we predict potential miRNA target hub mitochondrial genes at the transcriptome level. We also identified bortezomib and carfilzomib as the potential drugs for treatment in PAH. Finally, this study provides us with a new perspective on critical biomarkers and treatment strategies in PAH.
Highlights
Pulmonary arterial hypertension (PAH) is a severe and debilitating disorder with complex pathogenesis
hematoxylin and eosin (H&E) staining images of lung tissue samples from rats in different groups indicated that the animal model was successfully constructed (Figure 2)
differentially expressed proteins (DEPs) in PAH rats, Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to analyze the proteins that we have identified as mitochondrial DEPs
Summary
Pulmonary arterial hypertension (PAH) is a severe and debilitating disorder with complex pathogenesis. It is characterized by pulmonary arterioles’ pathological changes, leading to progressive increases in pulmonary vascular resistance, right heart failure, and becoming a significant complication of premature death from other diseases [1]. PAH has been proven with a prevalence range of 15 to 52 cases per million previously and significantly the highest in females above 65 years old [2]. Due to the unclear pathogenesis of PAH and the lack of more advanced diagnosis and treatment methods, the current aim of treatment is still to improve the quality of life in PAH patients. This study is aimed at exploring potential pathogenic molecules through proteomic studies, which will provide the necessary basis for improving the treatment of PAH
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