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Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNF?.

ABSTRACT: Atrial fibrillation (AF) is the most common supraventricular arrhythmia that, for unknown reasons, is linked to intense endurance exercise. Our studies reveal that 6 weeks of swimming or treadmill exercise improves heart pump function and reduces heart-rates. Exercise also increases vulnerability to AF in association with inflammation, fibrosis, increased vagal tone, slowed conduction velocity, prolonged cardiomyocyte action potentials and RyR2 phosphorylation (CamKII-dependent S2814) in the atria, without corresponding alterations in the ventricles. Microarray results suggest the involvement of the inflammatory cytokine, TNF?, in exercised-induced atrial remodelling. Accordingly, exercise induces TNF?-dependent activation of both NF?B and p38MAPK, while TNF? inhibition (with etanercept), TNF? gene ablation, or p38 inhibition, prevents atrial structural remodelling and AF vulnerability in response to exercise, without affecting the beneficial physiological changes. Our results identify TNF? as a key factor in the pathology of intense exercise-induced AF.

SUBMITTER: Aschar-Sobbi R

PROVIDER: S-EPMC4661059 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFα.

Aschar-Sobbi Roozbeh R Izaddoustdar Farzad F Korogyi Adam S AS Wang Qiongling Q Farman Gerrie P GP Yang FengHua F Yang Wallace W Dorian David D Simpson Jeremy A JA Tuomi Jari M JM Jones Douglas L DL Nanthakumar Kumaraswamy K Cox Brian B Wehrens Xander H T XH Dorian Paul P Backx Peter H PH

Nature communications 20150119

Atrial fibrillation (AF) is the most common supraventricular arrhythmia that, for unknown reasons, is linked to intense endurance exercise. Our studies reveal that 6 weeks of swimming or treadmill exercise improves heart pump function and reduces heart-rates. Exercise also increases vulnerability to AF in association with inflammation, fibrosis, increased vagal tone, slowed conduction velocity, prolonged cardiomyocyte action potentials and RyR2 phosphorylation (CamKII-dependent S2814) in the atr ...[more]

PMID: 25598495

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Project description:BackgroundSystemic inflammation is a potent contributor to increased seizure susceptibility. However, information regarding the effects of systemic inflammation on cerebral vascular integrity that influence neuron excitability is scarce. Necroptosis is closely associated with inflammation in various neurological diseases. In this study, necroptosis was hypothesized to be involved in the mechanism underlying sepsis-associated neuronal excitability in the cerebrovascular components (e.g., endothelia cells).MethodsLipopolysaccharide (LPS) was used to induce systemic inflammation. Kainic acid intraperitoneal injection was used to measure the susceptibility of the mice to seizure. The pharmacological inhibitors C87 and GSK872 were used to block the signaling of TNFα receptors and necroptosis. In order to determine the features of the sepsis-associated response in the cerebral vasculature and CNS, brain tissues of mice were obtained for assays of the necroptosis-related protein expression, and for immunofluorescence staining to identify morphological changes in the endothelia and glia. In addition, microdialysis assay was used to assess the changes in extracellular potassium and glutamate levels in the brain.ResultsSome noteworthy findings, such as increased seizure susceptibility and brain endothelial necroptosis, Kir4.1 dysfunction, and microglia activation were observed in mice following LPS injection. C87 treatment, a TNFα receptor inhibitor, showed considerable attenuation of increased kainic acid-induced seizure susceptibility, endothelial cell necroptosis, microglia activation and restoration of Kir4.1 protein expression in LPS-treated mice. Treatment with GSK872, a RIP3 inhibitor, such as C87, showed similar effects on these changes following LPS injection.ConclusionsThe findings of this study showed that TNFα-mediated necroptosis induced cerebrovascular endothelial damage, neuroinflammation and astrocyte Kir4.1 dysregulation, which may coalesce to contribute to the increased seizure susceptibility in LPS-treated mice. Pharmacologic inhibition targeting this necroptosis pathway may provide a promising therapeutic approach to the reduction of sepsis-associated brain endothelia cell injury, astrocyte ion channel dysfunction, and subsequent neuronal excitability.

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Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNF?.

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Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFα.

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