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Intracellular Na+-overload induces a proteomic and metabolomic remodeling of atrial myocytes leading to atrial cardiomyopathy and fibrillation

ABSTRACT: Aims Targeted therapies for atrial fibrillation (AF), the most common arrhythmia provoking heart failure and stroke, are urgently needed. However, the development of such therapies requires understanding of the cellular mechanisms that culminate in atrial cardiomyopathy (ACM) as a substrate for AF. Like in humans, increased persistent Na+ current leads to the development of ACM and spontaneous episodes of AF in mice. Here, we aim to identify and target the proteomic and metabolomic consequences of intracellular Na+-overload resulting in mitochondrial redox imbalance and contractile dysfunction of atrial myocytes (AMs). Methods and Results Transgenic mice expressing human gain-of-function mutant NaV1.5-F1759A channels in the fully redox-competent C57BL/6N background presented intracellular Na+-overload leading to AM hypertrophy, left atrial (LA) enlargement, contractile dysfunction and episodes of AF at early ages. Hence, we employed mass spectrometry of NaV1.5-F1759A LA myocardium to reveal the proteomic and metabolomic nature of ACM. In total we quantified 3,294 proteins across individual LA samples, of which 440 were differentially regulated in transgenic mice, including functionally relevant enzymes of key metabolic pathways. Metabolomic analyses confirmed changes in glycolytic and anaplerotic substrates, and identified a significant decrease in the cardioprotective antioxidant glutathione. Transgenic expression of the redox biosensor Grx1-roGFP in NaV1.5-F1759A AMs showed an oxidized glutathione redox potential indicative of mitochondrial ROS production upon catecholaminergic stimulation and field-pacing, which was not observed in control cells. Finally, we targeted the decreased expression of the sarcoplasmic reticulum protein junctophilin-2 by transgenic overexpression in NaV1.5-F1759A animals, which recued AM hypertrophy, LA contractility and AF burden in intracellular Na+-overload. Conclusions Atrial cardiomyopathy induced by intracellular Na+-overload in mice is characterized by profound cellular, proteomic and metabolomic changes culminating in mitochondrial redox imbalance and contractile dysfunction, which can be attenuated by restoring atrial junctophilin-2 expression.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Dr. Prasad Phapale

PROVIDER: MSV000098391 | MassIVE | Tue Jul 01 01:42:00 BST 2025

REPOSITORIES: MassIVE

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Project description:Background: Horses and humans are among the few mammals prone to developing spontaneous atrial fibrillation (AF), both suffering from high recurrence rates after treatment. Treatment resistance is often attributed to functional, structural, and metabolic remodeling of the atria. The aim of this explorative study was to evaluate the molecular pathways associated with early stages of AF in horses and to compare the AF proteomes between horses and humans. Methods: We performed data-independent acquisition mass spectrometry on myocardial biopsies collected from the right atrium (RA), left atrium (LA), and left ventricular chamber (LV) in horses with early stages of naturally occurring persistent AF and controls (n=8 in each group). Results: We identified a total of 3400 quantifiable proteins, several of which were differentially regulated between AF horses and controls (268 in RA, 324 in LA, and 284 in LV, p<0.05). Pathway enrichment analyses identified changes in metabolic, contractile, and extracellular matrix (ECM) proteins. Atrial hypocontractility and ECM remodeling were confirmed by echocardiography and histology, respectively. Key proteomic changes in horses with AF overlapped with human AF public datasets, underscoring the translational relevance of the equine AF model. Particularly, contractile proteins, such as cardiac troponins (TNNT2), myosin (MYH6) and tropomyosin (TPM2), along with metabolic regulators as heat shock protein family A (HSPA4) and Proteasome 26S Subunit, Non-ATPase 13 (PSMD13) were shared between horses and humans with AF. Moreover, a significant increase in several ECM glycoproteins was detected in both species, highlighting the importance of early ECM remodeling that extends beyond the fibrotic changes often associated with AF. Conclusion: The horse and human cardiac proteome share similar AF-related changes. Metabolic, functional, and structural protein changes identified in early-stage AF may provide clues to pharmacological targets for preventing AF-associated atrial remodeling and improving treatment success across species.

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Intracellular Na+-overload induces a proteomic and metabolomic remodeling of atrial myocytes leading to atrial cardiomyopathy and fibrillation

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