Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity

Hamilton, Shanna; Terentyev, Dmitry

doi:10.3389/fphys.2018.01517

Cited by 42 publications

(41 citation statements)

References 306 publications

(351 reference statements)

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“…However, during stress, hyperactivity of RyR2s has been associated with SCWs, which could translate into disturbances in membrane potential, i.e., delayed or early after depolarizations leading to malignant arrhythmias and sudden cardiac death (Belevych et al, 2012). Posttranslational modifications of the channel, including phosphorylation by PKA and/or CaMKII and oxidation of reactive cysteines, have been implicated in the RyR2 hyperactivity characteristic of cardiac disease and aging (Belevych et al, 2012; Zima et al, 2014; Hamilton and Terentyev, 2018, 2019). Consistent with this, treatment with ROS scavengers stabilized aberrant Ca 2+ release and lessened triggers for arrhythmia in conditions accompanied by oxidative stress, including heart failure (Terentyev et al, 2008) and myocardial infarction (Belevych et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Enhancing Autophagy Diminishes Aberrant Ca2+ Homeostasis and Arrhythmogenesis in Aging Rabbit Hearts

et al. 2019

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AimAging in humans is associated with a 10–40-fold greater incidence of sudden cardiac death from malignant tachyarrhythmia. We have reported that thiol oxidation of ryanodine receptors (RyR2s) by mitochondria-derived reactive oxygen species (mito-ROS) contributes to defective Ca2+ homeostasis in cardiomyocytes (CMs) from aging rabbit hearts. However, mechanisms responsible for the increase in mito-ROS in the aging heart remain poorly understood. Here we test the hypothesis that age-associated decrease in autophagy is a major contributor to enhanced mito-ROS production and thereby pro-arrhythmic disturbances in Ca2+ homeostasis.Methods and ResultsVentricular tissues from aged rabbits displayed significant downregulation of proteins involved in mitochondrial autophagy compared with tissues from young controls. Blocking autophagy with chloroquine increased total ROS production in primary rabbit CMs and mito-ROS production in HL-1 CMs. Furthermore, chloroquine treatment of HL-1 cells depolarized mitochondrial membrane potential (Δψm) to 50% that of controls. Blocking autophagy significantly increased oxidation of RyR2, resulting in enhanced propensity to pro-arrhythmic spontaneous Ca2+ release under β-adrenergic stimulation. Aberrant Ca2+ release was abolished by treatment with the mito-ROS scavenger mito-TEMPO. Importantly, the autophagy enhancer Torin1 and ATG7 overexpression reduced the rate of mito-ROS production and restored both Δψm and defective Ca2+ handling in CMs derived from aged rabbit hearts.ConclusionDecreased autophagy is a major cause of increased mito-ROS production in the aging heart. Our data suggest that promoting autophagy may reduce pathologic mito-ROS during normal aging and reduce pro-arrhythmic spontaneous Ca2+ release via oxidized RyR2s.

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Section: Discussionmentioning

confidence: 99%

Enhancing Autophagy Diminishes Aberrant Ca2+ Homeostasis and Arrhythmogenesis in Aging Rabbit Hearts

et al. 2019

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“…Genetic enhancement of mitochondrial antioxidant activity via overexpression of catalase reduced oxidative modifications and attenuated age-related changes in excitation-contraction coupling protein expression [139,140]. Electron and ROS scavenging or inhibition of mitochondrial oxidase has been shown to improve intracellular Ca 2+ handling and reduce arrhythmic potential in other disease models as well as aging, including heart failure and diabetic cardiomyopathy [9,12,45,141,142].…”

Section: Intracellular Ca2+ Homeostasis In the Aged Heartmentioning

confidence: 99%

“…We and others have comprehensively reviewed the function, post-translational modifications, and role of excitation-contraction coupling proteins in the development of cardiac arrhythmia [12,13,14,15,16]. In this case, we provide a more concentrated focus on aberrant intracellular Ca 2+ release and mechanisms of arrhythmogenesis that occur in the aged heart.…”

Section: Introductionmentioning

confidence: 99%

Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart

Hamilton

Terentyev

2019

IJMS

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Aging of the heart is associated with a blunted response to sympathetic stimulation, reduced contractility, and increased propensity for arrhythmias, with the risk of sudden cardiac death significantly increased in the elderly population. The altered cardiac structural and functional phenotype, as well as age-associated prevalent comorbidities including hypertension and atherosclerosis, predispose the heart to atrial fibrillation, heart failure, and ventricular tachyarrhythmias. At the cellular level, perturbations in mitochondrial function, excitation-contraction coupling, and calcium homeostasis contribute to this electrical and contractile dysfunction. Major determinants of cardiac contractility are the intracellular release of Ca2+ from the sarcoplasmic reticulum by the ryanodine receptors (RyR2), and the following sequestration of Ca2+ by the sarco/endoplasmic Ca2+-ATPase (SERCa2a). Activity of RyR2 and SERCa2a in myocytes is not only dependent on expression levels and interacting accessory proteins, but on fine-tuned regulation via post-translational modifications. In this paper, we review how aberrant changes in intracellular Ca2+ cycling via these proteins contributes to arrhythmogenesis in the aged heart.

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“…Sarcoplasmic reticulum Ca 2+ leak-induced changes in intracellular ROS, [Ca 2+ ] m and ΔΨ m may produce secondary effects on other key components of intracellular Ca 2+ handling machinery including SERCa2a, Na + /Ca 2+ exchanger and L-type Ca 2+ channels [8,33,68]. In the present study, we did not measure changes in activities of these complexes in caffeine-treated rat VMs or CPVT mouse VMs, nor did we measure intracellular [ATP].…”

Section: Limitationsmentioning

confidence: 75%

“…Parallel changes in RyR2 activity and mito-ROS production are hallmark features in cardiac pathology such as HF, MI, aging, or diabetic-induced cardiomyopathy [4,18,22,33,34,36,64,70]. We recently demonstrated that modulation of mito-Ca 2+ efficiently regulates RyR2 activity via mito-ROS [32].…”

Section: Discussionmentioning

confidence: 99%

Increased RyR2 activity is exacerbated by calcium leak-induced mitochondrial ROS

et al. 2020

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Cardiac disease is associated with deleterious emission of mitochondrial reactive oxygen species (mito-ROS), as well as enhanced oxidation and activity of the sarcoplasmic reticulum (SR) Ca 2+ release channel, the ryanodine receptor (RyR2). The transfer of Ca 2+ from the SR via RyR2 to mitochondria is thought to play a key role in matching increased metabolic demand during stress. In this study, we investigated whether augmented RyR2 activity results in self-imposed exacerbation of SR Ca 2+ leak, via altered SR-mitochondrial Ca 2+ transfer and elevated mito-ROS emission. Fluorescent indicators and spatially restricted genetic ROS probes revealed that both pharmacologically and genetically enhanced RyR2 activity, in ventricular myocytes from rats and catecholaminergic polymorphic ventricular tachycardia (CPVT) mice, respectively, resulted in increased ROS emission under β-adrenergic stimulation. Expression of mitochondrial Ca 2+ probe mtRCamp1h revealed diminished net mitochondrial [Ca 2+ ] with enhanced SR Ca 2+ leak, accompanied by depolarization of the mitochondrial matrix. While this may serve as a protective mechanism to prevent mitochondrial Ca 2+ overload, protection is not complete and enhanced mito-ROS emission resulted in oxidation of RyR2, further amplifying proarrhythmic SR Ca 2+ release. Importantly, the effects of augmented RyR2 activity could be attenuated by mitochondrial ROS scavenging, and experiments with dominant-negative paralogs of the mitochondrial Ca 2+ uniporter (MCU) supported the hypothesis that SR-mitochondria Ca 2+ transfer is essential for the increase in mito-ROS. We conclude that in a process whereby leak begets leak, augmented RyR2 activity modulates mitochondrial Ca 2+ handling, promoting mito-ROS emission and driving further channel activity in a proarrhythmic feedback cycle in the diseased heart.

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Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity

Cited by 42 publications

References 306 publications

Enhancing Autophagy Diminishes Aberrant Ca2+ Homeostasis and Arrhythmogenesis in Aging Rabbit Hearts

Enhancing Autophagy Diminishes Aberrant Ca2+ Homeostasis and Arrhythmogenesis in Aging Rabbit Hearts

Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart

Increased RyR2 activity is exacerbated by calcium leak-induced mitochondrial ROS

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