Myocardial proteomic profile in pulmonary arterial hypertension

Hołda, Mateusz K.; Stachowicz, Aneta; Suski, Maciej; Wojtysiak, Dorota; Sowińska, Natalia; Arent, Zbigniew; Palka, Natalia; Podolec, Piotr; Kopeć, Grzegorz

doi:10.1038/s41598-020-71264-8

Cited by 14 publications

(22 citation statements)

References 56 publications

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“…Proteomic characterization of the hypercholesterolemic myocardium in the current study revealed modest quantitative changes in a substantial number of proteins, which is in accordance with other proteomics-based studies of the left ventricle with impaired contractile function [23,24]. One of the most notable changes in the level of an individual protein was observed in the case of the downregulated expression of ACTB, an essential component of the non-contractile cytoskeleton system.…”

Section: Discussionsupporting

confidence: 90%

Diet-Induced Hypercholesterolemia Leads to Cardiac Dysfunction and Alterations in the Myocardial Proteome

Szabó

Pipicz

Sárközy

et al. 2022

IJMS

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Elevated blood cholesterol is a major risk factor for coronary heart disease. Moreover, direct effects on the myocardium also contribute to the adverse effects of hypercholesterolemia. Here, we investigated the effect of hypercholesterolemia on the cardiac proteome. Male Wistar rats were fed with a laboratory rodent chow supplemented with 2% cholesterol for 8 weeks to induce hypercholesterolemia. The protein expression data obtained from the proteomic characterization of left ventricular samples from normo- and hypercholesterolemic animals were subjected to gene ontology (GO) and protein interaction analyses. Elevated circulating cholesterol levels were accompanied by diastolic dysfunction in cholesterol-fed rats. The proteomic characterization of left ventricular samples revealed altered expression of 45 proteins due to hypercholesterolemia. Based on the Gene Ontology analysis, hypercholesterolemia was associated with disturbed expression of cytoskeletal and contractile proteins. Beta-actin was downregulated in the hypercholesterolemic myocardium, and established a prominent hub of the protein interaction network. Analysis of the unfiltered dataset revealed concordant downregulated expression patterns in proteins associated with the arrangement of the contractile system (e.g., cardiac-specific troponins and myosin complex), and in subunits of the mitochondrial respiratory chain. We conclude that the observed changes in the cardiac proteome may contribute to the development of diastolic dysfunction in hypercholesterolemia.

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Section: Discussionsupporting

confidence: 90%

Diet-Induced Hypercholesterolemia Leads to Cardiac Dysfunction and Alterations in the Myocardial Proteome

Szabó

Pipicz

Sárközy

et al. 2022

IJMS

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“…Additionally, miR-34 has been seen to have decreased expression in PAH [46,47], and let-7d, which has been identified as a potential biomarker for the presence and severity of PH in patients with SSc [48]. Similarly, the target genes driving the classification in an independent RNAseq dataset, TCF7L2, which ranked highest in importance has previously been seen to be differentially expressed in the lung tissue of IPAH patients [49] as well as in the cardiac muscle tissue in a rat model [50] Some of these target genes also showed weak to moderate correlation with available clinical features, such as lung function forced vital capacity (Supplementary Table 10).…”

Section: Discussionmentioning

confidence: 92%

A diagnostic miRNA signature for pulmonary arterial hypertension using a consensus machine learning approach

et al. 2021

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Background: Pulmonary arterial hypertension (PAH) is a rare but life shortening disease, the diagnosis of which is often delayed, and requires an invasive right heart catheterisation. Identifying diagnostic biomarkers may improve screening to identify patients at risk of PAH earlier and provide new insights into disease pathogenesis. MicroRNAs are small, non-coding molecules of RNA, previously shown to be dysregulated in PAH, and contribute to the disease process in animal models. Methods: Plasma from 64 treatment naïve patients with PAH and 43 disease and healthy controls were profiled for microRNA expression by Agilent Microarray. Following quality control and normalisation, the cohort was split into training and validation sets. Four separate machine learning feature selection methods were applied to the training set, along with a univariate analysis. Findings: 20 microRNAs were identified as putative biomarkers by consensus feature selection from all four methods. Two microRNAs (miR-636 and miR-187-5p) were selected by all methods and used to predict PAH diagnosis with high accuracy. Integrating microRNA expression profiles with their associated target mRNA revealed 61 differentially expressed genes verified in two independent, publicly available PAH lung tissue data sets. Two of seven potentially novel gene targets were validated as differentially expressed in vitro in human pulmonary artery smooth muscle cells. Interpretation: This consensus of multiple machine learning approaches identified two miRNAs that were able to distinguish PAH from both disease and healthy controls. These circulating miRNA, and their target genes may provide insight into PAH pathogenesis and reveal novel regulators of disease and putative drug targets.

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“…Besides, the significant overexpression of RPS27A could enhance the chemoresistance of CML cells to imatinib by trans-activating STAT3 ( Wang et al, 2016 ). However, several studies have identified considerable upregulation of RPS27A expression in the left ventricular myocardium of rats suffering from end-stage PAH (MCT-induced PAH rat model), and abnormal expression of RPS27A has been detected in the peripheral blood of patients with connective tissue disease-associated PAH, and its key regulatory role in the pathogenesis of PAH has been identified ( Hołda et al, 2020 ; Tu et al, 2022 ). Altogether, these findings confirmed that the blood-derived hub transcriptomes are associated with infiltrations of immune cells, hypoxia, and metabolism (glycolysis and fatty acid), which in turn regulates the aberrant vascular remodeling in PAH.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis and validation of novel immune and vascular remodeling related genes signature associated with drug interactions in pulmonary arterial hypertension

et al. 2022

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Background: Previous studies revealed that the gene signatures are associated with the modulation and pathogenesis of pulmonary arterial hypertension (PAH). However, identifying critical transcriptional signatures in the blood of PAH patients remains lacking.Methods: The differentially expressed transcriptional signatures in the blood of PAH patients were identified by a meta-analysis from four microarray datasets. Then we investigated the enrichment of gene ontology and KEGG pathways and identified top hub genes. Besides, we investigated the correlation of crucial hub genes with immune infiltrations, hallmark gene sets, and blood vessel remodeling genes. Furthermore, we investigated the diagnostic efficacy of essential hub genes and their expression validation in an independent cohort of PAH, and we validate the expression level of hub genes in monocrotaline (MCT) induced PAH rats’ model. Finally, we have identified the FDA-approved drugs that target the hub genes and their molecular docking.Results: We found 1,216 differentially expressed genes (DEGs), including 521 up-regulated and 695 down-regulated genes, in the blood of the PAH patients. The up-regulated DEGs are significantly associated with the enrichment of KEGG pathways mainly involved with immune regulation, cellular signaling, and metabolisms. We identified 13 master transcriptional regulators targeting the dysregulated genes in PAH. The STRING-based investigation identified the function of hub genes associated with multiple immune-related pathways in PAH. The expression levels of RPS27A, MAPK1, STAT1, RPS6, FBL, RPS3, RPS2, and GART are positively correlated with ssGSEA scores of various immune cells as positively correlated with the hallmark of oxidative stress. Besides, we found that these hub genes also regulate the vascular remodeling in PAH. Furthermore, the expression levels of identified hub genes showed good diagnostic efficacy in the blood of PAH, and we validated most of the hub genes are consistently dysregulated in an independent PAH cohort. Validation of hub genes expression level in the monocrotaline (MCT)-induced lung tissue of rats with PAH revealed that 5 screened hub genes (MAPK1, STAT1, TLR4, TLR2, GART) are significantly highly expressed in PAH rats, and 4 screened hub genes (RPS6, FBL, RPS3, and RPS2) are substantially lowly expressed in rats with PAH. Finally, we analyzed the interaction of hub proteins and FDA-approved drugs and revealed their molecular docking, and the results showed that MAPK1, TLR4, and GART interact with various drugs with appropriate binding affinity.Conclusion: The identified blood-derived key transcriptional signatures significantly correlate with immune infiltrations, hypoxia, glycolysis, and blood vessel remodeling genes. These findings may provide new insight into the diagnosis and treatment of PAH patients.

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Myocardial proteomic profile in pulmonary arterial hypertension

Cited by 14 publications

References 56 publications

Diet-Induced Hypercholesterolemia Leads to Cardiac Dysfunction and Alterations in the Myocardial Proteome

Diet-Induced Hypercholesterolemia Leads to Cardiac Dysfunction and Alterations in the Myocardial Proteome

A diagnostic miRNA signature for pulmonary arterial hypertension using a consensus machine learning approach

Comprehensive analysis and validation of novel immune and vascular remodeling related genes signature associated with drug interactions in pulmonary arterial hypertension

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