Dataset Information

Proteomic mapping of atrial and ventricular protein expression in patients with aortic valve stenosis

ABSTRACT: Objectives: The primary objective of this high-resolution proteomic study was to investigate patients with severe aortic valve stenosis (AVS) to detect novel biomarkers for diagnostic and/or therapeutic purposes. Background: Among patients with severe AVS, some are likely to rapidly progress with a higher mortality and benefit from prompt surgical or interventional care. To select these patients, novel disease-related biomarkers are needed. Methods: We used induced pluripotent stem cell derived cardiomyocytes as a relative quantification standard to profile the proteomes of formalin-fixed paraffin-embedded (FFPE) atria and left ventricles from 30 patients with AVS. Results: In total, 3370 proteins were quantified using high-resolution mass spectrometry. Statistical analysis revealed significant upregulation of 64 proteins in the atria and 27 proteins in the ventricles including several known chamber specific marker-proteins. Atrial upregulation of proteins that belong to the interstitial compartment or contribute to endocrine function was observed. To uncover disease related proteins, we compared our data to similar published datasets from healthy and diseased hearts. We performed gene set enrichment analyses to pinpoint global proteomic characteristics of a decompensated state of AVS with hypertrophy, like the downregulation of ventricular mitochondrial proteins and the development of ventricular fibrosis. Finally, we propose a set of high abundant proteins like LGALS3BP, TUBA4A, TINAGL1 and LAMA2 as well as SRL, FHL1 and ATP2A2 playing a crucial role in AVS-related heart disease. Conclusions: We established a reproducible workflow for high-resolution quantitative proteomics of FFPE myocardial samples and provide interesting candidate proteins with biomarker potential for AVS.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart, Stem Cell

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Christof Lenz

LAB HEAD: Christof Lenz

PROVIDER: PXD014297 | Pride | 2023-01-09

REPOSITORIES: Pride

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			Action	DRS
	H_Bohnenberger_UMG_051217_030118_heart_46_rep1_1.raw	Raw
	H_Bohnenberger_UMG_051217_030118_heart_46_rep1_2.raw	Raw
	H_Bohnenberger_UMG_051217_030118_heart_46_rep1_3.raw	Raw
	H_Bohnenberger_UMG_051217_030118_heart_46_rep1_4.raw	Raw
	H_Bohnenberger_UMG_051217_030118_heart_46_rep2_1.raw	Raw

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Proteomic mapping of atrial and ventricular heart tissue in patients with aortic valve stenosis.

Barbarics Boris B Eildermann Katja K Kaderali Lars L Cyganek Lukas L Plessmann Uwe U Bodemeyer Julius J Paul Thomas T Ströbel Philipp P Urlaub Henning H Tirilomis Theodorus T Lenz Christof C Bohnenberger Hanibal H

Scientific reports 20211222 1

Aortic valve stenosis (AVS) is one of the most common valve diseases in the world. However, detailed biological understanding of the myocardial changes in AVS hearts on the proteome level is still lacking. Proteomic studies using high-resolution mass spectrometry of formalin-fixed and paraffin-embedded (FFPE) human myocardial tissue of AVS-patients are very rare due to methodical issues. To overcome these issues this study used high resolution mass spectrometry in combination with a stem cell-de ...[more]

PMID: 34937869

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Project description:Note this data set has identical data files: Files GSM40994.txt and GSM40995.txt. GSE2240 contains two different experimental subsets:; 1) Comparison of atrial and ventricular gene expression (atrial tissue of patients with sinus rhythm vs. human left ventricular non-failing myocardium); The purpose of our investigation was to identify the transcriptional basis for ultrastructural and functional specialization of human atria and ventricles. Using exploratory microarray analysis (Affymetrix U133A+B), we detected 11,740 transcripts expressed in human heart, representing the most comprehensive report of the human myocardial transcriptome to date. Variation in gene expression between atria and ventricles accounted for the largest differences in this data set, as 3.300 and 2.974 transcripts showed higher expression in atria and ventricles, respectively. Functional classification based on Gene Ontology identified chamber-specific patterns of gene expression and provided molecular insights into the regional specialization of cardiomyocytes, correlating important functional pathways to transcriptional activity: Ventricular myocytes preferentially express genes satisfying contractile and energetic requirements, while atrial myocytes exhibit specific transcriptional activities related to neurohumoral function. In addition, several pro-fibrotic and apoptotic pathways were concentrated in atrial myocardium, substantiating the higher susceptibility of atria to programmed cell death and extracellular matrix remodelling observed in human and experimental animal models of heart failure. Differences in transcriptional profiles of atrial and ventricular myocardium thus provide molecular insights into myocardial cell diversity and distinct region-specific adaptations to physiological and pathophysiological conditions (Barth AS et al., Eur J Physiol, 2005). 2) Comparison of atrial gene expression in patients with permanent atrial fibrillation and sinus rhythm. Atrial fibrillation is associated with increased expression of ventricular myosin isoforms in atrial myocardium, regarded as part of a dedifferentiation process. Whether re-expression of ventricular isoforms in atrial fibrillation is restricted to transcripts encoding for contractile proteins is unknown. Therefore, this study compares atrial mRNA expression in patients with permanent atrial fibrillation to atrial mRNA expression of patients with sinus rhythm as well as to ventricular gene expression using Affymetrix U133 arrays. In atrial myocardium, we identified 1.434 genes deregulated in atrial fibrillation, the majority of which, including key elements of calcium-dependent signaling pathways, displayed down-regulation. Functional classification based on Gene Ontology provided the specific gene sets of the interdependent processes of structural, contractile and electrophysiological remodeling. In addition, we demonstrate for the first time a prominent up-regulation of transcripts involved in metabolic activities, suggesting an adaptive response to an increased metabolic demand in fibrillating atrial myocardium. Ventricular-predominant genes were five times more likely to be up-regulated in atrial fibrillation (174 genes up-regulated, 35 genes down-regulated), while atrial-specific transcripts were predominantly down-regulated (56 genes up-regulated, 564 genes down-regulated). Overall, in atrial myocardium, functional classes of genes characteristic of ventricular myocardium were found to be up-regulated (e.g. metabolic processes) while functional classes predominantly expressed in atrial myocardium were down-regulated in atrial fibrillation (e.g. signal transduction and cell communication). Therefore, dedifferentiation with adoption of a ventricular-like signature is a general feature of the fibrillating atrium, uncovering the transcriptional response pattern in pmAF (Barth AS et al., Circ Res, 2005).

Project description:GSE2240 contains two different experimental subsets: 1) Comparison of atrial and ventricular gene expression (atrial tissue of patients with sinus rhythm vs. human left ventricular non-failing myocardium) The purpose of our investigation was to identify the transcriptional basis for ultrastructural and functional specialization of human atria and ventricles. Using exploratory microarray analysis (Affymetrix U133A+B), we detected 11,740 transcripts expressed in human heart, representing the most comprehensive report of the human myocardial transcriptome to date. Variation in gene expression between atria and ventricles accounted for the largest differences in this data set, as 3.300 and 2.974 transcripts showed higher expression in atria and ventricles, respectively. Functional classification based on Gene Ontology identified chamber-specific patterns of gene expression and provided molecular insights into the regional specialization of cardiomyocytes, correlating important functional pathways to transcriptional activity: Ventricular myocytes preferentially express genes satisfying contractile and energetic requirements, while atrial myocytes exhibit specific transcriptional activities related to neurohumoral function. In addition, several pro-fibrotic and apoptotic pathways were concentrated in atrial myocardium, substantiating the higher susceptibility of atria to programmed cell death and extracellular matrix remodelling observed in human and experimental animal models of heart failure. Differences in transcriptional profiles of atrial and ventricular myocardium thus provide molecular insights into myocardial cell diversity and distinct region-specific adaptations to physiological and pathophysiological conditions (Barth AS et al., Eur J Physiol, 2005). 2) Comparison of atrial gene expression in patients with permanent atrial fibrillation and sinus rhythm. Atrial fibrillation is associated with increased expression of ventricular myosin isoforms in atrial myocardium, regarded as part of a dedifferentiation process. Whether re-expression of ventricular isoforms in atrial fibrillation is restricted to transcripts encoding for contractile proteins is unknown. Therefore, this study compares atrial mRNA expression in patients with permanent atrial fibrillation to atrial mRNA expression of patients with sinus rhythm as well as to ventricular gene expression using Affymetrix U133 arrays. In atrial myocardium, we identified 1.434 genes deregulated in atrial fibrillation, the majority of which, including key elements of calcium-dependent signaling pathways, displayed down-regulation. Functional classification based on Gene Ontology provided the specific gene sets of the interdependent processes of structural, contractile and electrophysiological remodeling. In addition, we demonstrate for the first time a prominent up-regulation of transcripts involved in metabolic activities, suggesting an adaptive response to an increased metabolic demand in fibrillating atrial myocardium. Ventricular-predominant genes were five times more likely to be up-regulated in atrial fibrillation (174 genes up-regulated, 35 genes down-regulated), while atrial-specific transcripts were predominantly down-regulated (56 genes up-regulated, 564 genes down-regulated). Overall, in atrial myocardium, functional classes of genes characteristic of ventricular myocardium were found to be up-regulated (e.g. metabolic processes) while functional classes predominantly expressed in atrial myocardium were down-regulated in atrial fibrillation (e.g. signal transduction and cell communication). Therefore, dedifferentiation with adoption of a ventricular-like signature is a general feature of the fibrillating atrium, uncovering the transcriptional response pattern in pmAF (Barth AS et al., Circ Res, 2005). Keywords = human myocardium Keywords = atrial fibrillation Keywords = sinus rhythm Keywords = left ventricular gene expression Keywords: other