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Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice

Stöckigt, Florian and Eichhorn, Lars and Beiert, Thomas and Knappe, Vincent and Radecke, Tobias and Steinmetz, Martin and Nickenig, Georg and Peeva, Viktoriya and Kudin, Alexei P. and Kunz, Wolfram S. and Berwanger, Carolin and Kamm, Lisa and Schultheis, Dorothea and Schlötzer-Schrehardt, Ursula and Clemen, Christoph S. and Schröder, Rolf and Schrickel, Jan W. (2020) Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice. PLoS One, 15 (3), e0228913. Public Library of Science (PLoS). doi: 10.1371/journal.pone.0228913. ISSN 1932-6203.

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Official URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228913

Abstract

Background Mutations in the human desmin gene (DES) cause autosomal-dominant and -recessive cardiomyopathies, leading to heart failure, arrhythmias, and AV blocks. We analyzed the effects of vascular pressure overload in a patient-mimicking p.R349P desmin knock-in mouse model that harbors the orthologue of the frequent human DES missense mutation p. R350P. Methods and results Transverse aortic constriction (TAC) was performed on heterozygous (HET) DES-p.R349P mice and wild-type (WT) littermates. Echocardiography demonstrated reduced left ventricular ejection fraction in HET-TAC (WT-sham: 69.5 ± 2.9%, HET-sham: 64.5 ± 4.7%, WTTAC: 63.5 ± 4.9%, HET-TAC: 55.7 ± 5.4%; p<0.01). Cardiac output was significantly reduced in HET-TAC (WT sham: 13088 ± 2385 μl/min, HET sham: 10391 ± 1349μl/min, WT-TAC: 8097 ± 1903μl/min, HET-TAC: 5793 ± 2517μl/min; p<0.01). Incidence and duration of AV blocks as well as the probability to induce ventricular tachycardias was highest in HET-TAC. We observed reduced mtDNA copy numbers in HET-TAC (WT-sham: 12546 ± 406, HET-sham: 13526 ± 781, WT-TAC: 11155 ± 3315, HET-TAC: 8649 ± 1582; p = 0.025), but no mtDNA deletions. The activity of respiratory chain complexes I and IV showed the greatest reductions in HET-TAC. Conclusion Pressure overload in HET mice aggravated the clinical phenotype of cardiomyopathy and resulted in mitochondrial dysfunction. Preventive avoidance of pressure overload/arterial hypertension in desminopathy patients might represent a crucial therapeutic measure.

Item URL in elib:https://elib.dlr.de/135972/
Document Type:Article
Title:Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice
Authors:
AuthorsInstitution or Email of AuthorsAuthor's ORCID iD
Stöckigt, FlorianDepartment of Cardiology, University Hospital Bonn, Bonn, Germanyhttps://orcid.org/0000-0002-0885-679X
Eichhorn, LarsDepartment of Anesthesiology, University Hospital Bonn, Bonn, GermanyUNSPECIFIED
Beiert, ThomasDepartment of Cardiology, University Hospital Bonn, Bonn, GermanyUNSPECIFIED
Knappe, VincentDepartment of Cardiology, University Hospital Bonn, Bonn, GermanyUNSPECIFIED
Radecke, TobiasDepartment of Cardiology, University Hospital Essen, Hufelandstraße, Essen, GermanyUNSPECIFIED
Steinmetz, MartinDepartment of Cardiology, University Hospital Essen, Hufelandstraße, Essen, GermanyUNSPECIFIED
Nickenig, GeorgDepartment of Cardiology, University Hospital Bonn, Bonn, GermanyUNSPECIFIED
Peeva, ViktoriyaInstitute of Experimental Epileptology and Cognition Research, Bonn, GermanyUNSPECIFIED
Kudin, Alexei P.Institute of Experimental Epileptology and Cognition Research, Bonn, GermanyUNSPECIFIED
Kunz, Wolfram S.Institute of Experimental Epileptology and Cognition Research, Bonn, GermanyUNSPECIFIED
Berwanger, CarolinMuscle and Bone Metabolism Department, DLR, Institute of Aerospace Medicine, Cologne, GermanyUNSPECIFIED
Kamm, LisaInstitute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nu¨rnberg, Schwabachanlage, Erlangen, GermanyUNSPECIFIED
Schultheis, DorotheaInstitute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nu¨rnberg, Schwabachanlage, Erlangen, GermanyUNSPECIFIED
Schlötzer-Schrehardt, UrsulaDepartment of Opthalmology, University Hospital Erlangen, Friedrich-Alexander University ErlangenNu¨rnberg, Schwabachanlage, Erlangen, GermanyUNSPECIFIED
Clemen, Christoph S.Institute of Aerospace Medicine, German Aerospace Center (DLR), 51147 Cologne, GermanyUNSPECIFIED
Schröder, RolfInstitute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nu¨rnberg, Schwabachanlage, Erlangen, GermanyUNSPECIFIED
Schrickel, Jan W.Department of Cardiology, University Hospital Bonn, Bonn, GermanyUNSPECIFIED
Date:3 March 2020
Journal or Publication Title:PLoS One
Refereed publication:Yes
Open Access:Yes
Gold Open Access:Yes
In SCOPUS:Yes
In ISI Web of Science:Yes
Volume:15
DOI :10.1371/journal.pone.0228913
Page Range:e0228913
Publisher:Public Library of Science (PLoS)
ISSN:1932-6203
Status:Published
Keywords:autosomal-dominant desminopathies, DES-p.R349P,
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Space
HGF - Program Themes:Research under Space Conditions
DLR - Research area:Raumfahrt
DLR - Program:R FR - Research under Space Conditions
DLR - Research theme (Project):R - Vorhaben Systemphysiologie (old)
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine > Muscle and Bone Metabolism
Deposited By: Arndt, Carina
Deposited On:08 Sep 2020 13:06
Last Modified:08 Sep 2020 13:06

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