| Title: | Proteomics couples electrical remodelling to inflammation in a murine model of heart failure with sinus node dysfunction |
| Journal: | Cardiovascular Research |
| Published: | 25 Apr 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38661182/ |
| DOI: | https://doi.org/10.1093/cvr/cvae054 |
Publication 9840
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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.</p>
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.</p>
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.</p>
23 Authors
- Konstantin Kahnert
- Luca Soattin
- Robert W Mills
- Claire Wilson
- Svetlana Maurya
- Andrea Sorrentino
- Sami Al-Othman
- Roman Tikhomirov
- Yordi J van de Vegte
- Finn B Hansen
- Jonathan Achter
- Wei Hu
- Min Zi
- Matthew Smith
- Pim van der Harst
- Morten S Olesen
- Kristine Boisen Olsen
- Jytte Banner
- Thomas H L Jensen
- Henggui Zhang
- Mark R Boyett
- Alicia D'Souza
- Alicia Lundby
1 Application
| Application ID | Title |
|---|---|
| 12010 | Determinants of human cardiac structure and function and relation with outcome |
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