MassIVE MSV000098391

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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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Description

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. [doi:10.25345/C5XS5JW00] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Atrial fibrillation ; atrial cardiomyopathy ; intracellular sodium overload, junctophillin-2 ; proteomic and metabolomic profiling ; reactive oxygen species ; DatasetType:Metabolomics

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Principal Investigators:
(in alphabetical order) 		Dr. Prasad Phapale, Leibniz-Institut fuer Analytische Wissenschaften-ISAS-e.V., Germany
Submitting User: Kasarla04
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