Direct proteomic and high-resolution microscopy biopsy analysis identifies distinct ventricular fates in severe aortic stenosis

Brandenburg, Sören; Otto, Lena; Schönberger, Hanne-Lena; Jacob, Christoph F.; Paulke, N; Beuthner, Bo Eric; Topci, Rodi; Kohl, Tobias; Neuenroth, Lisa; Kutschka, Ingo; Urlaub, Henning; Kück, Fabian; Leha, Andreas; Friede, Tim; Seidler, Tim; Jacobshagen, Claudius; Toischer, Karl; Puls, Miriam; Hasenfuß, Gerd; Lenz, Christof; Lehnart, Stephan E.

doi:10.1016/j.yjmcc.2022.08.363

Cited by 13 publications

(8 citation statements)

References 54 publications

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“…Comparison of our results with a recent proteomic study on AS subtypes with different disease burdens showed excellent agreement in the overlap of quantified proteins in general ( Fig S2A ) and also of AS- but not MR-specific significantly regulated proteins ( Fig S2B and C ) ( Brandenburg et al, 2022 ). The higher numbers of significantly regulated proteins in our study can be explained by the deeper proteomic coverage and also overall larger sample size.…”

Section: Resultssupporting

confidence: 85%

“…Integrative analyses were performed on proteomic data and clinical imaging (cardiac magnetic resonance imaging) phenotypes. also of AS-but not MR-specific significantly regulated proteins (Fig S2B and C) (Brandenburg et al, 2022). The higher numbers of significantly regulated proteins in our study can be explained by the deeper proteomic coverage and also overall larger sample size.…”

Section: Quantitative Proteome Comparison Between Disease and Healthy...mentioning

confidence: 50%

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Disease- and sex-specific differences in patients with heart valve disease: a proteome study

et al. 2023

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Pressure overload in patients with aortic valve stenosis and volume overload in mitral valve regurgitation trigger specific forms of cardiac remodeling; however, little is known about similarities and differences in myocardial proteome regulation. We performed proteome profiling of 75 human left ventricular myocardial biopsies (aortic stenosis = 41, mitral regurgitation = 17, and controls = 17) using high-resolution tandem mass spectrometry next to clinical and hemodynamic parameter acquisition. In patients of both disease groups, proteins related to ECM and cytoskeleton were more abundant, whereas those related to energy metabolism and proteostasis were less abundant compared with controls. In addition, disease group–specific and sex-specific differences have been observed. Male patients with aortic stenosis showed more proteins related to fibrosis and less to energy metabolism, whereas female patients showed strong reduction in proteostasis-related proteins. Clinical imaging was in line with proteomic findings, showing elevation of fibrosis in both patient groups and sex differences. Disease- and sex-specific proteomic profiles provide insight into cardiac remodeling in patients with heart valve disease and might help improve the understanding of molecular mechanisms and the development of individualized treatment strategies.

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Section: Resultssupporting

confidence: 85%

Section: Quantitative Proteome Comparison Between Disease and Healthy...mentioning

confidence: 50%

Disease- and sex-specific differences in patients with heart valve disease: a proteome study

et al. 2023

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“…The promising approach we used in this study, proteomics, is a powerful tool for pathogenesis exploration and drug target identification. Meanwhile, novel DIA-based proteomics technology promises the robust and accurate quantification of proteins, and is increasingly being applied in cardiovascular disease research [ 53 , 54 ]. Our findings have important clinical implications, but several limitations of this study need to be mentioned.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Pathogenic Mechanism of Ciprofloxacin in Aortic Aneurysm and Dissection by an Integrated Proteomics and Network Pharmacology Strategy

Chen

Wang

et al. 2023

JCM

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Aortic aneurysm and dissection (AAD) is a life-threatening disease worldwide. Recently, fluoroquinolones have been reported to significantly increase the risk of AAD. This study aimed to investigate the potential functional mechanism and molecular targets of fluoroquinolones in relation to AAD by an integrated proteomic and network pharmacology strategy. A total of 1351 differentially expressed proteins were identified in human aortic vascular smooth muscle cells (VSMCs) after ciprofloxacin (CIP) stimulation. The functional analysis emphasized the important roles of metabolism, extracellular matrix homeostasis, mitochondrial damage, focal adhesion, and apoptosis in CIP-stimulated VSMCs. CIP targets were predicted with online databases and verified by molecular docking. Protein–protein interaction (PPI) analysis and module construction of the 34 potential CIP targets and 37 selected hub molecules after CIP stimulation identified four critical target proteins in the module: PARP1, RAC1, IGF1R and MKI67. Functional analysis of the PPI module showed that the MAPK signalling pathway, focal adhesion, apoptosis, regulation of actin cytoskeleton, and PI3K-Akt signalling pathway were significantly enriched. Our results will provide novel insights into the pathogenic mechanism of fluoroquinolones in aortic diseases.

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“…While high fraction workflows such as the one by Schulte et al (Schulte et al, 2023) offer very high levels of detail, they also require significant amounts of starting material to yield at least low microgram protein amounts per fraction in order to support reproducible sample preparation and recovery. We aimed for a protein input amount ranging from 35-70 µg, which is consistent with the protein quantities recovered from human patient biopsies (Brandenburg et al, 2022) or single mouse organs. Assuming a roughly equal distribution of protein across the BNE, each of the 35 fractions generated in our approach will contain 1-2 µg of protein.…”

Section: Mcp Workflow Design and Developmentmentioning

confidence: 99%

mini-Complexome Profiling (mCP), an FDR-controlled workflow for global targeted detection of protein complexes

Amedei,

Paul,

Foo

et al. 2024

Preprint

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Introduction: Co-fractionation mass spectrometry couples native-like separations of protein/protein complexes with mass spectrometric proteome analysis for global characterization of protein networks. The technique allows for both de novo detection of complexes and for the detection of subtle changes in their protein composition. The typical requirement for fine-grained fractionation of >80 fractions, however, translates into significant demands on sample quantity and mass spectrometric instrument time, and represents a significant barrier to experimental replication and the use of scarce sample material (ex. Patient biopsies). Methods: We developed mini-Complexome Profiling (mCP), a streamlined workflow with reduced requirements for fractionation and, thus, biological material and laboratory and instrument time. Soluble and membrane-associated protein complexes are extracted from biological material under mild conditions, and fractionated by Blue Native electrophoresis using commercial equipment. Each fraction is analyzed by data independent acquisition mass-spectrometry, and known protein complexes are detected based on the coelution of known components using a novel R package with a controlled false discovery rate approach. The tool is available to the community on a GitHub repository. Results: mCP was benchmarked using HEK293 cell lysate and exhibited performance similar to established workflows, but from a significantly reduced number of fractions. We then challenged mCP by performing comparative complexome analysis of cardiomyocytes isolated from different chambers from a single mouse heart, where we identified subtle chamber-specific changes in mitochondrial OxPhos complexes. Discussion: The reduced sample and instrument time requirements open up new applications of co-fractionation mass spectrometry, specifically for the analysis of sparse samples such as human patient biopsies. The ability to identify subtle changes between similar tissue types (left/right ventricular and atrial cardiomyocytes) serves as a proof of principle for comparative analysis of mild/asymptomatic disease states.

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Direct proteomic and high-resolution microscopy biopsy analysis identifies distinct ventricular fates in severe aortic stenosis

Cited by 13 publications

References 54 publications

Disease- and sex-specific differences in patients with heart valve disease: a proteome study

Disease- and sex-specific differences in patients with heart valve disease: a proteome study

Investigation of the Pathogenic Mechanism of Ciprofloxacin in Aortic Aneurysm and Dissection by an Integrated Proteomics and Network Pharmacology Strategy

mini-Complexome Profiling (mCP), an FDR-controlled workflow for global targeted detection of protein complexes

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