TY - JOUR

T1 - Proteomics couples electrical remodelling to inflammation in a murine model of heart failure with sinus node dysfunction

AU - Kahnert, Konstantin

AU - Soattin, Luca

AU - Mills, Robert W

AU - Wilson, Claire

AU - Maurya, Svetlana

AU - Sorrentino, Andrea

AU - Al-Othman, Sami

AU - Tikhomirov, Roman

AU - van de Vegte, Yordi J

AU - Hansen, Finn B

AU - Achter, Jonathan

AU - Hu, Wei

AU - Zi, Min

AU - Smith, Matthew

AU - van der Harst, Pim

AU - Olesen, Morten S

AU - Olsen, Kristine Boisen

AU - Banner, Jytte

AU - Jensen, Thomas H L

AU - Zhang, Henggui

AU - Boyett, Mark R

AU - D'Souza, Alicia

AU - Lundby, Alicia

N1 - © The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

U2 - 10.1093/cvr/cvae054

DO - 10.1093/cvr/cvae054

M3 - Journal article

C2 - 38661182

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

M1 - cvae054

ER -