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  1. Article ; Online: A New Window onto the Pacemaker of the Heart, the Sinus Node, Provided by Quantitative Proteomics and Single-Nucleus Transcriptomics.

    Boyett, Mark / Lundby, Alicia

    Journal of cellular immunology

    2020  Volume 2, Issue 2, Page(s) 38–41

    Language English
    Publishing date 2020-04-27
    Publishing country United States
    Document type Journal Article
    ISSN 2689-2812
    ISSN (online) 2689-2812
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Proteome-wide profiling and mapping of post translational modifications in human hearts.

    Bagwan, Navratan / El Ali, Henrik H / Lundby, Alicia

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 2184

    Abstract: Post translational modifications (PTMs) are covalent modifications of proteins that can range from small chemical modifications to addition of entire proteins. PTMs contribute to regulation of protein function and thereby greatly increase the functional ... ...

    Abstract Post translational modifications (PTMs) are covalent modifications of proteins that can range from small chemical modifications to addition of entire proteins. PTMs contribute to regulation of protein function and thereby greatly increase the functional diversity of the proteome. In the heart, a few well-studied PTMs, such as phosphorylation and glycosylation, are known to play essential roles for cardiac function. Yet, only a fraction of the ~ 300 known PTMs have been studied in a cardiac context. Here we investigated the proteome-wide map of PTMs present in human hearts by utilizing high-resolution mass spectrometry measurements and a suite of PTM identification algorithms. Our approach led to identification of more than 150 different PTMs across three of the chambers in human hearts. This finding underscores that decoration of cardiac proteins by PTMs is much more diverse than hitherto appreciated and provides insights in cardiac protein PTMs not yet studied. The results presented serve as a catalogue of which PTMs are present in human hearts and outlines the particular protein and the specific amino acid modified, and thereby provides a detail-rich resource for exploring protein modifications in human hearts beyond the most studied PTMs.
    MeSH term(s) Amino Acid Sequence ; Amino Acids/metabolism ; Humans ; Myocardium/metabolism ; Oxidation-Reduction ; Peptides/chemistry ; Peptides/metabolism ; Phosphorylation ; Protein Processing, Post-Translational ; Proteome/chemistry ; Proteome/metabolism ; Proteomics
    Chemical Substances Amino Acids ; Peptides ; Proteome
    Language English
    Publishing date 2021-01-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-81986-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Molecular switches in signaling networks as a mechanism of action for oncogenic mutations in proximity of tyrosine residues.

    Emdal, Kristina B / Lundby, Alicia

    Molecular & cellular oncology

    2019  Volume 7, Issue 1, Page(s) 1692643

    Abstract: We developed a mass spectrometry-based proteomics strategy to study oncogenic phosphotyrosine signaling networks in tissues. We outlined epidermal growth factor-dependent phosphotyrosine signaling in lung tissue and discovered that cancer mutations in ... ...

    Abstract We developed a mass spectrometry-based proteomics strategy to study oncogenic phosphotyrosine signaling networks in tissues. We outlined epidermal growth factor-dependent phosphotyrosine signaling in lung tissue and discovered that cancer mutations in vicinity of phosphotyrosine sites can induce molecular switches in recruited protein complexes, which ultimately alter the signaling outcome of the network activation.
    Language English
    Publishing date 2019-12-06
    Publishing country United States
    Document type Journal Article
    ISSN 2372-3556
    ISSN 2372-3556
    DOI 10.1080/23723556.2019.1692643
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  4. Article ; Online: Oncotherapeutic Protein Kinase Inhibitors Associated With Pro-Arrhythmic Liability.

    Ye, Johan Z / Hansen, Finn B / Mills, Robert W / Lundby, Alicia

    JACC. CardioOncology

    2021  Volume 3, Issue 1, Page(s) 88–97

    Abstract: Background: Ibrutinib is a protein kinase inhibitor that has been widely successful in treating multiple common variations of B-cell cancers. However, an unfortunate side effect of ibrutinib is that it predisposes patients to development of atrial ... ...

    Abstract Background: Ibrutinib is a protein kinase inhibitor that has been widely successful in treating multiple common variations of B-cell cancers. However, an unfortunate side effect of ibrutinib is that it predisposes patients to development of atrial fibrillation.
    Objectives: The purpose of this study was to assess other commonly prescribed protein kinase inhibitors for similar pro-arrhythmic liability.
    Methods: This study comprehensively evaluated data from the U.S. Food and Drug Administration adverse events reporting system and determined the reporting of cardiac arrhythmia attributed to kinase inhibitor therapy using a multivariable logistic regression model. We evaluated 3,663,300 case reports containing 23,067 cases of atrial fibrillation and 66,262 cases of cardiac arrhythmia. In total, 32 protein kinase inhibitors were evaluated, almost all of which are oncotherapeutics.
    Results: Seven protein kinase inhibitors were associated with a significant increase in the odds of atrial fibrillation (ibrutinib, ponatinib, nilotinib, ribociclib, trametinib, osimertinib, and idelalisib). Assessment of broader pro-arrhythmic toxicity suggested a ventricular-specific liability for nilotinib and a bradyarrhythmia risk with alectinib and crizotinib.
    Conclusions: Compounds that result in the inhibition of a number of protein kinases are associated with an increased risk of cardiac rhythm disturbances. The mechanisms driving the arrhythmogenic effects remain to be discovered, but this study presents an important step in identifying and prioritizing the study of these protein kinase signaling pathways.
    Language English
    Publishing date 2021-03-16
    Publishing country United States
    Document type Journal Article
    ISSN 2666-0873
    ISSN (online) 2666-0873
    DOI 10.1016/j.jaccao.2021.01.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Beta-blocker/ACE inhibitor therapy differentially impacts the steady state signaling landscape of failing and non-failing hearts.

    Sorrentino, Andrea / Bagwan, Navratan / Linscheid, Nora / Poulsen, Pi C / Kahnert, Konstantin / Thomsen, Morten B / Delmar, Mario / Lundby, Alicia

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 4760

    Abstract: Heart failure is a multifactorial disease that affects an estimated 38 million people worldwide. Current pharmacotherapy of heart failure with reduced ejection fraction (HFrEF) includes combination therapy with angiotensin-converting enzyme inhibitors ( ... ...

    Abstract Heart failure is a multifactorial disease that affects an estimated 38 million people worldwide. Current pharmacotherapy of heart failure with reduced ejection fraction (HFrEF) includes combination therapy with angiotensin-converting enzyme inhibitors (ACEi) and β-adrenergic receptor blockers (β-AR blockers), a therapy also used as treatment for non-cardiac conditions. Our knowledge of the molecular changes accompanying treatment with ACEi and β-AR blockers is limited. Here, we applied proteomics and phosphoproteomics approaches to profile the global changes in protein abundance and phosphorylation state in cardiac left ventricles consequent to combination therapy of β-AR blocker and ACE inhibitor in HFrEF and control hearts. The phosphorylation changes induced by treatment were profoundly different for failing than for non-failing hearts. HFrEF was characterized by profound downregulation of mitochondrial proteins coupled with derangement of β-adrenergic and pyruvate dehydrogenase signaling. Upon treatment, phosphorylation changes consequent to HFrEF were reversed. In control hearts, treatment mainly led to downregulation of canonical PKA signaling. The observation of divergent signaling outcomes depending on disease state underscores the importance of evaluating drug effects within the context of the specific conditions present in the recipient heart.
    MeSH term(s) Adrenergic beta-Antagonists/pharmacology ; Adrenergic beta-Antagonists/therapeutic use ; Angiotensin Receptor Antagonists/therapeutic use ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Heart ; Heart Failure/drug therapy ; Heart Failure/metabolism ; Humans ; Stroke Volume/physiology
    Chemical Substances Adrenergic beta-Antagonists ; Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors
    Language English
    Publishing date 2022-03-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-08534-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data.

    Ye, Johan Z / Delmar, Mario / Lundby, Alicia / Olesen, Morten S

    Clinical genetics

    2019  Volume 96, Issue 6, Page(s) 506–514

    Abstract: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is one of the most common causes of sudden cardiac death in young people. Patients diagnosed with ARVC may experience increased likelihood of development of anxiety and depression, emphasizing the ... ...

    Abstract Arrhythmogenic right ventricular cardiomyopathy (ARVC) is one of the most common causes of sudden cardiac death in young people. Patients diagnosed with ARVC may experience increased likelihood of development of anxiety and depression, emphasizing the need for accurate diagnosis. To assist future genetic diagnosis and avoidance of misdiagnosis, we evaluated the reported monogenic disease-causing variants in ARVD/C Genetic Variants Database, Human Gene Mutation Database, and ClinVar. Within the aforementioned databases, 630 monogenic disease-causing variants from 18 genes were identified. In the genome Aggregation Database, 226 of these were identified; 68 of which were found at greater than expected prevalence. Furthermore, 37/226 genetic variants were identified amongst the 409 000 UK biobank participants, 23 were not associated with ARVC. Among the 14 remaining variants, 13 were previously found with greater than expected prevalence for a monogenic variant. Nevertheless, they were associated with serious cardiac phenotypes, suggesting that these 13 variants may be disease-modifiers of ARVC, rather than monogenic disease-causing. In summary, more than 10% of variants previously reported to cause ARVC were found unlikely to be associated with highly penetrant monogenic forms of ARVC. Notably, all variants in OBSCN and MYBPC3 were found, making these unlikely to be monogenic causes of ARVC.
    MeSH term(s) Arrhythmogenic Right Ventricular Dysplasia/genetics ; Cohort Studies ; Databases, Genetic ; Genetic Variation ; Genome, Human ; Humans ; Myocardium/pathology ; Phenotype ; Prevalence ; Proteomics
    Language English
    Publishing date 2019-08-19
    Publishing country Denmark
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 221209-2
    ISSN 1399-0004 ; 0009-9163
    ISSN (online) 1399-0004
    ISSN 0009-9163
    DOI 10.1111/cge.13621
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 413: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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  7. Article ; Online: Outlining cardiac ion channel protein interactors and their signature in the human electrocardiogram.

    Maurya, Svetlana / Mills, Robert W / Kahnert, Konstantin / Chiang, David Y / Bertoli, Giorgia / Lundegaard, Pia R / Duran, Marta Perez-Hernandez / Zhang, Mingliang / Rothenberg, Eli / George, Alfred L / MacRae, Calum A / Delmar, Mario / Lundby, Alicia

    Nature cardiovascular research

    2023  Volume 2, Issue 7, Page(s) 673–692

    Abstract: Protein-protein interactions are essential for normal cellular processes and signaling events. Defining these interaction networks is therefore crucial for understanding complex cellular functions and interpretation of disease-associated gene variants. ... ...

    Abstract Protein-protein interactions are essential for normal cellular processes and signaling events. Defining these interaction networks is therefore crucial for understanding complex cellular functions and interpretation of disease-associated gene variants. We need to build a comprehensive picture of the interactions, their affinities and interdependencies in the specific organ to decipher hitherto poorly understood signaling mechanisms through ion channels. Here we report the experimental identification of the ensemble of protein interactors for 13 types of ion channels in murine cardiac tissue. Of these, we validated the functional importance of ten interactors on cardiac electrophysiology through genetic knockouts in zebrafish, gene silencing in mice, super-resolution microscopy and patch clamp experiments. Furthermore, we establish a computational framework to reconstruct human cardiomyocyte ion channel networks from deep proteome mapping of human heart tissue and human heart single-cell gene expression data. Finally, we integrate the ion channel interactome with human population genetics data to identify proteins that influence the electrocardiogram (ECG). We demonstrate that the combined channel network is enriched for proteins influencing the ECG, with 44% of the network proteins significantly associated with an ECG phenotype. Altogether, we define interactomes of 13 major cardiac ion channels, contextualize their relevance to human electrophysiology and validate functional roles of ten interactors, including two regulators of the sodium current (epsin-2 and gelsolin). Overall, our data provide a roadmap for our understanding of the molecular machinery that regulates cardiac electrophysiology.
    Language English
    Publishing date 2023-07-13
    Publishing country England
    Document type Journal Article
    ISSN 2731-0590
    ISSN (online) 2731-0590
    DOI 10.1038/s44161-023-00294-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Phosphoproteomics taken to heart.

    Lundby, Alicia / Olsen, Jesper V

    Cell cycle (Georgetown, Tex.)

    2013  Volume 12, Issue 17, Page(s) 2707–2708

    MeSH term(s) Animals ; Heart/physiology ; Phosphoproteins/chemistry ; Proteomics ; Receptors, Adrenergic, beta/physiology ; Signal Transduction
    Chemical Substances Phosphoproteins ; Receptors, Adrenergic, beta
    Language English
    Publishing date 2013-08-06
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.4161/cc.25883
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5881: Show issues Location:
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  9. Article ; Online: Proteomics couples electrical remodelling to inflammation in a murine model of heart failure with sinus node dysfunction.

    Kahnert, Konstantin / Soattin, Luca / Mills, Robert W / Wilson, Claire / Maurya, Svetlana / Sorrentino, Andrea / Al-Othman, Sami / Tikhomirov, Roman / van de Vegte, Yordi J / Hansen, Finn B / Achter, Jonathan / Hu, Wei / Zi, Min / Smith, Matthew / van der Harst, Pim / Olesen, Morten S / Olsen, Kristine Boisen / Banner, Jytte / Jensen, Thomas H L /
    Zhang, Henggui / Boyett, Mark R / D'Souza, Alicia / Lundby, Alicia

    Cardiovascular research

    2024  

    Abstract: Aims: In patients with heart failure (HF), concomitant sinus node dysfunction (SND) is an important predictor of mortality, yet its molecular underpinnings are poorly understood. Using proteomics, this study aimed to dissect the protein and ... ...

    Abstract Aims: In patients with heart failure (HF), concomitant sinus node dysfunction (SND) is an important predictor of mortality, yet its molecular underpinnings are poorly understood. Using proteomics, this study aimed to dissect the protein and phosphorylation remodelling within the sinus node in an animal model of HF with concurrent SND.
    Methods and results: We acquired deep sinus node proteomes and phosphoproteomes in mice with heart failure and SND and report extensive remodelling. Intersecting the measured (phospho)proteome changes with human genomics pharmacovigilance data, highlighted downregulated proteins involved in electrical activity such as the pacemaker ion channel, Hcn4. We confirmed the importance of ion channel downregulation for sinus node physiology using computer modelling. Guided by the proteomics data, we hypothesized that an inflammatory response may drive the electrophysiological remodeling underlying SND in heart failure. In support of this, experimentally induced inflammation downregulated Hcn4 and slowed pacemaking in the isolated sinus node. From the proteomics data we identified proinflammatory cytokine-like protein galectin-3 as a potential target to mitigate the effect. Indeed, in vivo suppression of galectin-3 in the animal model of heart failure prevented SND.
    Conclusion: Collectively, we outline the protein and phosphorylation remodeling of SND in heart failure, we highlight a role for inflammation in electrophysiological remodelling of the sinus node, and we present galectin-3 signalling as a target to ameliorate SND in heart failure.
    Language English
    Publishing date 2024-04-25
    Publishing country England
    Document type Journal Article
    ZDB-ID 80340-6
    ISSN 1755-3245 ; 0008-6363
    ISSN (online) 1755-3245
    ISSN 0008-6363
    DOI 10.1093/cvr/cvae054
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 565: Show issues Location:
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  10. Article ; Online: Cardiac fibroblast sub-types

    Herum, Kate Møller / Weng, Guangzheng / Kahnert, Konstantin / Waikel, Rebekah / Milburn, Greg / Conger, Autumn / Anaya, Paul / Campbell, Kenneth S / Lundby, Alicia / Won, Kyoung Jae / Brakebusch, Cord

    Matrix biology plus

    2022  Volume 15, Page(s) 100113

    Abstract: Many heart diseases are associated with fibrosis, but it is unclear whether different types of heart disease correlate with different subtypes of activated fibroblasts and to which extent such diversity is modeled ... ...

    Abstract Many heart diseases are associated with fibrosis, but it is unclear whether different types of heart disease correlate with different subtypes of activated fibroblasts and to which extent such diversity is modeled during
    Language English
    Publishing date 2022-06-06
    Publishing country Netherlands
    Document type Journal Article
    ISSN 2590-0285
    ISSN (online) 2590-0285
    DOI 10.1016/j.mbplus.2022.100113
    Database MEDical Literature Analysis and Retrieval System OnLINE

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