Direct proteomic and high-resolution microscopy biopsy analysis identifies distinct ventricular fates in severe aortic stenosis
2022 | journal article. A publication with affiliation to the University of Göttingen.
Jump to: Cite & Linked | Documents & Media | Details | Version history
Cite this publication
Direct proteomic and high-resolution microscopy biopsy analysis identifies distinct ventricular fates in severe aortic stenosis
Brandenburg, S. ; Drews, L.; Schönberger, H.-L.; Jacob, C. F.; Paulke, N. J.; Beuthner, B. E. & Topci, R. et al. (2022)
Journal of Molecular and Cellular Cardiology, 173 pp. 1-15. DOI: https://doi.org/10.1016/j.yjmcc.2022.08.363
Documents & Media
Details
- Authors
- Brandenburg, Sören ; Drews, Lena; Schönberger, Hanne-Lea; Jacob, Christoph F.; Paulke, Nora Josefine; Beuthner, Bo E.; Topci, Rodi; Kohl, Tobias ; Neuenroth, Lisa; Kutschka, Ingo ; Lehnart, Stephan E.
- Abstract
- The incidence of aortic valve stenosis (AS), the most common reason for aortic valve replacement (AVR), increases with population ageing. While untreated AS is associated with high mortality, different hemodynamic subtypes range from normal left-ventricular function to severe heart failure. However, the molecular nature underlying four different AS subclasses, suggesting vastly different myocardial fates, is unknown. Here, we used direct proteomic analysis of small left-ventricular biopsies to identify unique protein expression profiles and subtype-specific AS mechanisms. Left-ventricular endomyocardial biopsies were harvested from patients during transcatheter AVR, and inclusion criteria were based on echocardiographic diagnosis of severe AS and guideline-defined AS-subtype classification: 1) normal ejection fraction (EF)/high-gradient; 2) low EF/high-gradient; 3) low EF/low-gradient; and 4) paradoxical low-flow/low-gradient AS. Samples from non-failing donor hearts served as control. We analyzed 25 individual left-ventricular biopsies by data-independent acquisition mass spectrometry (DIA-MS), and 26 biopsies by histomorphology and cardiomyocytes by STimulated Emission Depletion (STED) superresolution microscopy. Notably, DIA-MS reliably detected 2273 proteins throughout each individual left-ventricular biopsy, of which 160 proteins showed significant abundance changes between AS-subtype and non-failing samples including the cardiac ryanodine receptor (RyR2). Hierarchical clustering segregated unique proteotypes that identified three hemodynamic AS-subtypes. Additionally, distinct proteotypes were linked with AS-subtype specific differences in cardiomyocyte hypertrophy. Furthermore, superresolution microscopy of immunolabeled biopsy sections showed subcellular RyR2-cluster fragmentation and disruption of the functionally important association with transverse tubules, which occurred specifically in patients with systolic dysfunction and may hence contribute to depressed left-ventricular function in AS.
- Issue Date
- 2022
- Journal
- Journal of Molecular and Cellular Cardiology
- Project
- EXC 2067: Multiscale Bioimaging
SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente
SFB 1190 | Z02: Massenspektrometrie-basierte Proteomanalyse
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz
SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion
SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur
SFB 1002 | S02: Hochauflösende Fluoreszenzmikroskopie und integrative Datenanalyse - Organization
- Klinik für Kardiologie und Pneumologie ; Herzforschungszentrum Göttingen ; Deutsches Zentrum für Herz-Kreislauf-Forschung e.V. ; Institut für Klinische Chemie ; Klinik für Thorax-, Herz- und Gefäßchirurgie ; Max-Planck-Institut für Multidisziplinäre Naturwissenschaften ; Institut für Medizinische Statistik ; Klinik für Kardiologie und Pneumologie ; Universitätsmedizin Göttingen
- Working Group
- RG Hasenfuß (Transition zur Herzinsuffizienz)
RG Lehnart (Cellular Biophysics and Translational Cardiology Section)
RG Toischer (Kardiales Remodeling)
RG Urlaub (Bioanalytische Massenspektrometrie)
RG Brandenburg
RG Lenz - ISSN
- 0022-2828
- Language
- English