ORCID Profile
0000-0002-1612-6041
Current Organisation
IT University of Copenhagen
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-09-2022
DOI: 10.1161/CIRCULATIONAHA.122.060454
Abstract: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by high propensity to life-threatening arrhythmias and progressive loss of heart muscle. More than 40% of reported genetic variants linked to ARVC reside in the PKP2 gene, which encodes the PKP2 protein (plakophilin-2). We describe a comprehensive characterization of the ARVC molecular landscape as determined by high-resolution mass spectrometry, RNA sequencing, and transmission electron microscopy of right ventricular biopsy s les obtained from patients with ARVC with PKP2 mutations and left ventricular ejection fraction %. S les from healthy relatives served as controls. The observations led to experimental work using multiple imaging and biochemical techniques in mice with a cardiac-specific deletion of Pkp2 studied at a time of preserved left ventricular ejection fraction and in human induced pluripotent stem cell–derived PKP2-deficient myocytes. S les from patients with ARVC present a loss of nuclear envelope integrity, molecular signatures indicative of increased DNA damage, and a deficit in transcripts coding for proteins in the electron transport chain. Mice with a cardiac-specific deletion of Pkp2 also present a loss of nuclear envelope integrity, which leads to DNA damage and subsequent excess oxidant production (O 2 .– and H 2 O 2 ), the latter increased further under mechanical stress (isoproterenol or exercise). Increased oxidant production and DNA damage is recapitulated in human induced pluripotent stem cell–derived PKP2-deficient myocytes. Furthermore, PKP2-deficient cells release H 2 O 2 into the extracellular environment, causing DNA damage and increased oxidant production in neighboring myocytes in a paracrine manner. Treatment with honokiol increases SIRT3 (mitochondrial nicotinamide adenine dinucleotide–dependent protein deacetylase sirtuin-3) activity, reduces oxidant levels and DNA damage in vitro and in vivo, reduces collagen abundance in the right ventricular free wall, and has a protective effect on right ventricular function. Loss of nuclear envelope integrity and subsequent DNA damage is a key substrate in the molecular pathology of ARVC. We show transcriptional downregulation of proteins of the electron transcript chain as an early event in the molecular pathophysiology of the disease (before loss of left ventricular ejection fraction %), which associates with increased oxidant production (O 2 .– and H 2 O 2 ). We propose therapies that limit oxidant formation as a possible intervention to restrict DNA damage in ARVC.
Publisher: Springer Science and Business Media LLC
Date: 22-06-2014
DOI: 10.1038/NG.3014
Publisher: Cold Spring Harbor Laboratory
Date: 09-01-2020
DOI: 10.1101/2020.01.08.897595
Abstract: The study of human cardiac pathologies often relies on research conducted in model organisms to gain molecular insight into disease and to develop novel treatment strategies however, translating findings from model organisms back to human can present a significant challenge, in part due to a lack of knowledge about the differences across species in cardiac protein abundances and their interactions. Here we set out to bridge this knowledge gap by presenting a global analysis of cardiac protein expression profiles in humans and commonly used model organisms. Using quantitative mass spectrometry-based proteomics, we measured the abundance of ~7,000 proteins in s les from the separate chambers of human, pig, horse, rat, mouse and zebrafish hearts. This knowledgebase of cardiac protein signatures is accessible through an online database at: atlas.cardiacproteomics.com. Quantitative comparison of the protein profiles support the pig as model organism of choice for arrhythmogenic right ventricular cardiomyopathy whereas comparison of profiles from the two-chambered zebrafish heart suggests a better resemblance to the right side of mammalian hearts. This proteomics resource facilitates translational prospect of cardiac studies from model organisms to humans by enabling direct comparison of disease-linked protein networks across species.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2013
DOI: 10.1038/NG.2610
Location: United States of America
No related grants have been discovered for Alicia Lundby.