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Kcne4 deletion sex-specifically predisposes to cardiac arrhythmia via testosterone-dependent impairment of RISK/SAFE pathway induction in aged mice.

ABSTRACT: Sudden cardiac death (SCD) is associated with both electrical and ischemic substrates, and is a major cause of ischemic heart disease mortality worldwide. Male sex predisposes to SCD but the underlying mechanisms are incompletely understood. KCNE4, a cardiac arrhythmia-associated potassium channel ?-subunit, is upregulated by 5?-dihydrotestosterone (DHT). Thus, ventricular Kcne4 expression is low in young adult female mice, but high in males and postmenopausal (12+ months) females. Despite causing a sex-independent electrical substrate at 13 months of age (22% QT prolongation in both males and females; P?

SUBMITTER: Hu Z

PROVIDER: S-EPMC5974354 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Kcne4 deletion sex-specifically predisposes to cardiac arrhythmia via testosterone-dependent impairment of RISK/SAFE pathway induction in aged mice.

Hu Zhaoyang Z Wei Wei W Zhou Leng L Chen Mou M Abbott Geoffrey W GW

Scientific reports 20180529 1

Sudden cardiac death (SCD) is associated with both electrical and ischemic substrates, and is a major cause of ischemic heart disease mortality worldwide. Male sex predisposes to SCD but the underlying mechanisms are incompletely understood. KCNE4, a cardiac arrhythmia-associated potassium channel β-subunit, is upregulated by 5α-dihydrotestosterone (DHT). Thus, ventricular Kcne4 expression is low in young adult female mice, but high in males and postmenopausal (12+ months) females. Despite causi ...[more]

PMID: 29844497

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Project description:KCNE5 is an X-linked gene encoding KCNE5, an ancillary subunit to voltage-gated potassium (KV) channels. Human KCNE5 mutations are associated with atrial fibrillation (AF)- and Brugada syndrome (BrS)-induced cardiac arrhythmias that can arise from increased potassium current in cardiomyocytes. Seeking to establish underlying molecular mechanisms, we created and studied Kcne5 knockout ( Kcne5-/0) mice. Intracardiac ECG revealed that Kcne5 deletion caused ventricular premature beats, increased susceptibility to induction of polymorphic ventricular tachycardia (60 vs. 24% in Kcne5+/0 mice), and 10% shorter ventricular refractory period. Kcne5 deletion increased mean ventricular myocyte KV current density in the apex and also in the subpopulation of septal myocytes that lack fast transient outward current ( Ito,f). The current increases arose from an apex-specific increase in slow transient outward current-1 ( IKslow,1) (conducted by KV1.5) and Ito,f (conducted by KV4) and an increase in IKslow,2 (conducted by KV2.1) in both apex and septum. Kcne5 protein localized to the intercalated discs in ventricular myocytes, where KV2.1 was also detected in both Kcne5-/0 and Kcne5+/0 mice. In HL-1 cardiac cells and human embryonic kidney cells, KCNE5 and KV2.1 colocalized at the cell surface, but predominantly in intracellular vesicles, suggesting that Kcne5 deletion increases IK,slow2 by reducing KV2.1 intracellular sequestration. The human AF-associated mutation KCNE5-L65F negative shifted the voltage dependence of KV2.1-KCNE5 channels, increasing their maximum current density >2-fold, whereas BrS-associated KCNE5 mutations produced more subtle negative shifts in KV2.1 voltage dependence. The findings represent the first reported native role for Kcne5 and the first demonstrated Kcne regulation of KV2.1 in mouse heart. Increased KV current is a manifestation of KCNE5 disruption that is most likely common to both mouse and human hearts, providing a plausible mechanistic basis for human KCNE5-linked AF and BrS.-David, J.-P., Lisewski, U., Crump, S. M., Jepps, T. A., Bocksteins, E., Wilck, N., Lossie, J., Roepke, T. K., Schmitt, N., Abbott, G. W. Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia.

Project description:AimsPeroxisome proliferator-activated receptor-γ coactivators PGC1α and PGC1β modulate mitochondrial biogenesis and energy homeostasis. The function of these transcriptional coactivators is impaired in obesity, insulin resistance, and type 2 diabetes. We searched for transcriptomic, lipidomic, and electrophysiological alterations in PGC1β(-/-) hearts potentially associated with increased arrhythmic risk in metabolic diseases.Methods and resultsMicroarray analysis in mouse PGC1β(-/-) hearts confirmed down-regulation of genes related to oxidative phosphorylation and the electron transport chain and up-regulation of hypertrophy- and hypoxia-related genes. Lipidomic analysis showed increased levels of the pro-arrhythmic and pro-inflammatory lipid, lysophosphatidylcholine. PGC1β(-/-) mouse electrocardiograms showed irregular heartbeats and an increased incidence of polymorphic ventricular tachycardia following isoprenaline infusion. Langendorff-perfused PGC1β(-/-) hearts showed action potential alternans, early after-depolarizations, and ventricular tachycardia. PGC1β(-/-) ventricular myocytes showed oscillatory resting potentials, action potentials with early and delayed after-depolarizations, and burst firing during sustained current injection. They showed abnormal diastolic Ca(2+) transients, whose amplitude and frequency were increased by isoprenaline, and Ca(2+) currents with negatively shifted inactivation characteristics, with increased window currents despite unaltered levels of CACNA1C RNA transcripts. Inwardly and outward rectifying K(+) currents were all increased. Quantitiative RT-PCR demonstrated increased SCN5A, KCNA5, RYR2, and Ca(2+)-calmodulin dependent protein kinase II expression.ConclusionPGC1β(-/-) hearts showed a lysophospholipid-induced cardiac lipotoxicity and impaired bioenergetics accompanied by an ion channel remodelling and altered Ca(2+) homeostasis, converging to produce a ventricular arrhythmic phenotype particularly during adrenergic stress. This could contribute to the increased cardiac mortality associated with both metabolic and cardiac disease attributable to lysophospholipid accumulation.

Dataset Information

Kcne4 deletion sex-specifically predisposes to cardiac arrhythmia via testosterone-dependent impairment of RISK/SAFE pathway induction in aged mice.

Publications

Kcne4 deletion sex-specifically predisposes to cardiac arrhythmia via testosterone-dependent impairment of RISK/SAFE pathway induction in aged mice.

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