Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII‐constitutive phosphorylation of RyR2 at site S2814

Mazzocchi, Gabriela; Sommese, Leandro Matías; Palomeque, Julieta; Felice, Juan Ignacio; Carlo, Mariano Nahuel Di; Fainstein, Diego; González, Pedro Horacio; Contreras, Paola; Skapura, Darlene G.; McCauley, Mark D.; Lascano, Elena C.; Negroni, Jorge A.; Kranias, Evangelia G.; Wehrens, Xander H.T.; Valverde, Carlos; Mattiazzi, Alicia

doi:10.1113/jp271622

Cited by 22 publications

(60 citation statements)

References 61 publications

(94 reference statements)

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“…Cells were loaded with 10 μ m Fluo‐3 AM for 20 min at room temperature excited with a 488 nm (argon laser) and fluorescence was collected at >515 nm (Mazzocchi et al . ). Each image consisted of 512 line scans obtained at 4 ms intervals.…”

Section: Methodsmentioning

confidence: 97%

Calcium‐calmodulin‐dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance

Federico

Portiansky

Sommese

et al. 2017

The Journal of Physiology

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The impact of cardiac apoptosis in pre-diabetic stages of diabetic cardiomyopathy is unknown. We show that myocytes from fructose-rich diet (FRD) animals exhibit arrhythmias produced by exacerbated Ca /calmodulin-protein kinase (CaMKII) activity, ryanodine receptor 2 (RyR2) phosphorylation and sarcoplasmic reticulum (SR) Ca leak. We tested the hypothesis that this mechanism also underlies cardiac apoptosis in pre-diabetes. We generated a pre-diabetic model in FRD mice. FRD mice showed an increase in oxidative stress, hypertrophy and systolic dysfunction. FRD myocytes exhibited enhanced SR Ca spontaneous events in the absence of SR Ca load alterations vs. control-diet (CD) myocytes. In HEK293 cells, hyperglycaemia significantly enhanced [ H]ryanodine binding and CaMKII phosphorylation of RyR2-S2814 residue vs. normoglycaemia. CaMKII inhibition prevented hyperglycaemia-induced alterations. FRD also evoked cardiac apoptosis in WT mice vs. CD-WT mice. Co-treatment with the reactive oxygen species scavenger Tempol prevented FRD-induced apoptosis in WT mice. In contrast, FRD enhanced oxidative stress but not apoptosis in FRD-SR-AIP mice, in which a CaMKII inhibitor is targeted to the SR. FRD produced mitochondrial membrane depolarization in WT mice but not in S2814A mice, in which the CaMKII phosphorylation site on RyR2 was ablated. Furthermore, FRD decreased mitochondrial area, mean Feret diameter and mean SR-mitochondrial distance vs. CD-WT hearts. This remodelling was prevented in AC3I mice, with cardiac-targeted CaMKII inhibition. CaMKII phosphorylation of RyR2, SR Ca leak and mitochondrial membrane depolarization are critically involved in the apoptotic pathway of the pre-diabetic heart. The FRD-induced decrease in SR-mitochondrial distance is likely to additionally favour Ca transit between the two organelles.

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Section: Methodsmentioning

confidence: 97%

Calcium‐calmodulin‐dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance

Federico

Portiansky

Sommese

et al. 2017

The Journal of Physiology

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“…This model has been validated by us and others. 26,27 For details, refer to the supplementary material.…”

Section: Human Cardiac Myocyte Mathematical Modelmentioning

confidence: 99%

Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity

Gonano

Sepúlveda

Morell

et al. 2018

Circ J

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Background: It has been shown that carvedilol and its non β-blocking analog, VK-II-86, inhibit spontaneous Ca 2+ release from the sarcoplasmic reticulum (SR). The aim of this study is to determine whether carvedilol and VK-II-86 suppress ouabain-induced arrhythmogenic Ca 2+ waves and apoptosis in cardiac myocytes. Methods and Results: Rat cardiac myocytes were exposed to toxic doses of ouabain (50 µmol/L). Cell length (contraction) was monitored in electrically stimulated and non-stimulated conditions. Ouabain treatment increased contractility, frequency of spontaneous contractions and apoptosis compared to control cells. Carvedilol (1 µmol/L) or VK-II-86 (1 µmol/L) did not affect ouabain-induced inotropy, but significantly reduced the frequency of Ca 2+ waves, spontaneous contractions and cell death evoked by ouabain treatment. This antiarrhythmic effect was not associated with a reduction in Ca 2+ calmodulin-dependent protein kinase II (CaMKII) activity, phospholamban and ryanodine receptor phosphorylation or SR Ca 2+ load. Similar results could be replicated in human cardiomyocytes derived from stem cells and in a mathematical model of human myocytes. Conclusions: Carvedilol and VK-II-86 are effective to prevent ouabain-induced apoptosis and spontaneous contractions indicative of arrhythmogenic activity without affecting inotropy and demonstrated to be effective in human models, thus emerging as a therapeutic tool for the prevention of digitalis-induced arrhythmias and cardiac toxicity.

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“…Triggered activity is strongly related to calcium overload, and it can be attributed to reduced levels of SERCA 2A in our experimental model [33,44]. SERCA 2A is the main ATPase responsible for calcium reuptake at the sarcoplasmic reticulum [45,46]. Other homeostatic mechanisms regulate calcium, but the SERCA 2A reduction described here could be a strong indicator of calcium-triggered events during ischemia/reperfusion.…”

Section: Discussionmentioning

confidence: 67%

Reperfusion Arrhythmias Increase after Superior Cervical Ganglionectomy Due to Conduction Disorders and Changes in Repolarization

Prado

Muñoz

Altamirano

et al. 2020

IJMS

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Pharmacological concentrations of melatonin reduce reperfusion arrhythmias, but less is known about the antiarrhythmic protection of the physiological circadian rhythm of melatonin. Bilateral surgical removal of the superior cervical ganglia irreversibly suppresses melatonin rhythmicity. This study aimed to analyze the cardiac electrophysiological effects of the loss of melatonin circadian oscillation and the role played by myocardial melatonin membrane receptors, SERCA2A, TNFα, nitrotyrosine, TGFβ, KATP channels, and connexin 43. Three weeks after bilateral removal of the superior cervical ganglia or sham surgery, the hearts were isolated and submitted to ten minutes of regional ischemia followed by ten minutes of reperfusion. Arrhythmias, mainly ventricular tachycardia, increased during reperfusion in the ganglionectomy group. These hearts also suffered an epicardial electrical activation delay that increased during ischemia, action potential alternants, triggered activity, and dispersion of action potential duration. Hearts from ganglionectomized rats showed a reduction of the cardioprotective MT2 receptors, the MT1 receptors, and SERCA2A. Markers of nitroxidative stress (nitrotyrosine), inflammation (TNFα), and fibrosis (TGFβ and vimentin) did not change between groups. Connexin 43 lateralization and the pore-forming subunit (Kir6.1) of KATP channels increased in the experimental group. We conclude that the loss of the circadian rhythm of melatonin predisposes the heart to suffer cardiac arrhythmias, mainly ventricular tachycardia, due to conduction disorders and changes in repolarization.

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Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII‐constitutive phosphorylation of RyR2 at site S2814

Cited by 22 publications

References 61 publications

Calcium‐calmodulin‐dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance

Calcium‐calmodulin‐dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance

Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity

Reperfusion Arrhythmias Increase after Superior Cervical Ganglionectomy Due to Conduction Disorders and Changes in Repolarization

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