Dataset Information

SK channel enhancers attenuate Ca2+-dependent arrhythmia in hypertrophic hearts by regulating mito-ROS-dependent oxidation and activity of RyR.

ABSTRACT:

Aims

Plasmamembrane small conductance Ca2+-activated K+?(SK) channels were implicated in ventricular arrhythmias in infarcted and failing hearts. Recently, SK channels were detected in the inner mitochondria membrane (IMM) (mSK), and their activation protected from acute ischaemia-reperfusion injury by reducing intracellular levels of reactive oxygen species (ROS). We hypothesized that mSK play an important role in regulating mitochondrial function in chronic cardiac diseases. We investigated the role of mSK channels in Ca2+-dependent ventricular arrhythmia using rat model of cardiac hypertrophy induced by banding of the ascending aorta thoracic aortic banding (TAB).

Methods and results

Dual Ca2+?and membrane potential optical mapping of whole hearts derived from TAB rats revealed that membrane-permeable SK enhancer NS309 (2??M) improved aberrant Ca2+?homeostasis and abolished VT/VF induced by ?-adrenergic stimulation. Using whole cell patch-clamp and confocal Ca2+?imaging of cardiomyocytes derived from TAB hearts (TCMs) we found that membrane-permeable SK enhancers NS309 and CyPPA (10??M) attenuated frequency of spontaneous Ca2+?waves and delayed afterdepolarizations. Furthermore, mSK inhibition enhanced (UCL-1684, 1??M); while activation reduced mitochondrial ROS production in TCMs measured with MitoSOX. Protein oxidation assays demonstrated that increased oxidation of ryanodine receptors (RyRs) in TCMs was reversed by SK enhancers. Experiments in permeabilized TCMs showed that SK enhancers restored SR Ca2+?content, suggestive of substantial improvement in RyR function.

Conclusion

These data suggest that enhancement of mSK channels in hypertrophic rat hearts protects from Ca2+-dependent arrhythmia and suggest that the protection is mediated via decreased mitochondrial ROS and subsequent decreased oxidation of reactive cysteines in RyR, which ultimately leads to stabilization of RyR-mediated Ca2+?release.

SUBMITTER: Kim TY

PROVIDER: S-EPMC5852621 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Publications

SK channel enhancers attenuate Ca2+-dependent arrhythmia in hypertrophic hearts by regulating mito-ROS-dependent oxidation and activity of RyR.

Kim Tae Yun TY Terentyeva Radmila R Roder Karim H F KH Li Weiyan W Liu Man M Greener Ian I Hamilton Shanna S Polina Iuliia I Murphy Kevin R KR Clements Richard T RT Dudley Samuel C SC Koren Gideon G Choi Bum-Rak BR Terentyev Dmitry D

Cardiovascular research 20170301 3

<h4>Aims</h4>Plasmamembrane small conductance Ca2+-activated K+ (SK) channels were implicated in ventricular arrhythmias in infarcted and failing hearts. Recently, SK channels were detected in the inner mitochondria membrane (IMM) (mSK), and their activation protected from acute ischaemia-reperfusion injury by reducing intracellular levels of reactive oxygen species (ROS). We hypothesized that mSK play an important role in regulating mitochondrial function in chronic cardiac diseases. We investi ...[more]

PMID: 28096168

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Project description:Cardiac dysfunction in heart failure (HF) and diabetic cardiomyopathy (DCM) is associated with aberrant intracellular Ca2+ handling and impaired mitochondrial function accompanied with reduced mitochondrial calcium concentration (mito-[Ca2+]). Pharmacological or genetic facilitation of mito-Ca2+ uptake was shown to restore Ca2+ transient amplitude in DCM and HF, improving contractility. However, recent reports suggest that pharmacological enhancement of mito-Ca2+ uptake can exacerbate ryanodine receptor-mediated spontaneous sarcoplasmic reticulum (SR) Ca2+ release in ventricular myocytes (VMs) from diseased animals, increasing propensity to stress-induced ventricular tachyarrhythmia. To test whether chronic recovery of mito-[Ca2+] restores systolic Ca2+ release without adverse effects in diastole, we overexpressed mitochondrial Ca2+ uniporter (MCU) in VMs from male rat hearts with hypertrophy induced by thoracic aortic banding (TAB). Measurement of mito-[Ca2+] using genetic probe mtRCamp1h revealed that mito-[Ca2+] in TAB VMs paced at 2 Hz under β-adrenergic stimulation is lower compared with shams. Adenoviral 2.5-fold MCU overexpression in TAB VMs fully restored mito-[Ca2+]. However, it failed to improve cytosolic Ca2+ handling and reduce proarrhythmic spontaneous Ca2+ waves. Furthermore, mitochondrial-targeted genetic probes MLS-HyPer7 and OMM-HyPer revealed a significant increase in emission of reactive oxygen species (ROS) in TAB VMs with 2.5-fold MCU overexpression. Conversely, 1.5-fold MCU overexpression in TABs, that led to partial restoration of mito-[Ca2+], reduced mitochondria-derived reactive oxygen species (mito-ROS) and spontaneous Ca2+ waves. Our findings emphasize the key role of elevated mito-ROS in disease-related proarrhythmic Ca2+ mishandling. These data establish nonlinear mito-[Ca2+]/mito-ROS relationship, whereby partial restoration of mito-[Ca2+] in diseased VMs is protective, whereas further enhancement of MCU-mediated Ca2+ uptake exacerbates damaging mito-ROS emission.NEW & NOTEWORTHY Defective intracellular Ca2+ homeostasis and aberrant mitochondrial function are common features in cardiac disease. Here, we directly compared potential benefits of mito-ROS scavenging and restoration of mito-Ca2+ uptake by overexpressing MCU in ventricular myocytes from hypertrophic rat hearts. Experiments using novel mito-ROS and Ca2+ biosensors demonstrated that mito-ROS scavenging rescued both cytosolic and mito-Ca2+ homeostasis, whereas moderate and high MCU overexpression demonstrated disparate effects on mito-ROS emission, with only a moderate increase in MCU being beneficial.

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Dataset Information

SK channel enhancers attenuate Ca2+-dependent arrhythmia in hypertrophic hearts by regulating mito-ROS-dependent oxidation and activity of RyR.

Aims

Methods and results

Conclusion

Publications

SK channel enhancers attenuate Ca2+-dependent arrhythmia in hypertrophic hearts by regulating mito-ROS-dependent oxidation and activity of RyR.

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