Reduction in Na+ current by angiotensin II is mediated by PKCα in mouse and human-induced pluripotent stem cell–derived cardiomyocytes

Mathieu, Sophie; Khoury, Nabil; Rivard, Katy; Gélinas, Roselle; Goyette, Philippe; Paradis, Pierre; Nemer, Mona; Fiset, Céline

doi:10.1016/j.hrthm.2016.02.015

Cited by 16 publications

(31 citation statements)

References 34 publications

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“…ISO and AngII were used to treat NRCMs to mimic the overactivation of sympathetic nervous system and rennin–angiotensin–aldosterone system in heart failure. AngII was reported to reduce I Na through H 2 O 2 ‐mediated transcription reduction, and by activation of splice factor RBM25 and LUC7L3 . While another report showed that the chronic AngII type 1 receptor activation reduced I Na density by about 60%, but it could not be explained by the slightly reduced Nav1.5 mRNA level, 39 these data suggest that different mechanisms are involved in AngII‐mediated downregulation of I Na .…”

Section: Discussionmentioning

confidence: 84%

Calcium‐dependent Nedd4‐2 upregulation mediates degradation of the cardiac sodium channel Nav1.5: implications for heart failure

Luo

Ning

et al. 2017

Acta Physiologica

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Section: Discussionmentioning

confidence: 84%

Calcium‐dependent Nedd4‐2 upregulation mediates degradation of the cardiac sodium channel Nav1.5: implications for heart failure

Luo

Ning

et al. 2017

Acta Physiologica

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“…Our results are consistent with a recent study shows that PKCα mediates angiotensin II-induced I Na reduction. 34 It is unclear if the PKCα effects on the channel were the result of direct modification of the channel or an unidentified indirect effect, however. A scheme of NADH signaling cascades regulating Na v 1.5 is shown in Figure 7.…”

Section: Discussionmentioning

confidence: 99%

Role of protein kinase C in metabolic regulation of the cardiac Na+ channel

et al. 2017

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Background NADH increases in cardiomyopathy, activates protein kinase C (PKC), upregulates mitochondrial reactive oxygen species (mitoROS), and downregulates the cardiac Na+ channel (Nav1.5). Objective The objective was to determine how NADH signals downregulation of Nav1.5. Methods Isolated mouse cardiomyocytes were used for patch clamp recording and to monitor mitoROS with MitoSOX™ Red. HEK293 cells were used for transient transfections. HEK293 cells stably expressing human Nav1.5 were utilized for single channel recording, whole-cell patch clamp recording, activity measurements of phospholipase C and D (PLD), channel protein purification, and co-immunoprecipitation with PKC isoforms. HL-1 cells were used for mitochondria isolation. Results NADH enhanced PLD activity (1.6±0.1-fold, P<0.01) and activated PKCδ. Activated PKCδ translocated to mitochondria and upregulated mitoROS (2.8±0.3-fold, P<0.01) by enhancing the activities of mitochondrial complexes I, II and IV (1.1- to 1.5-fold, P<0.01). PKCδ also interacted with Nav1.5 to downregulate Na+ current (INa). Reduction in INa by activated PKCδ was prevented by antioxidants and by mutating the known PKC phosphorylation site S1503. At the single channel level, the mechanism of current reduction by PKC and recovery by PKA was a change in single channel conductance. Conclusion NADH activated PKCδ by enhancing PLD activity. PKCδ modulated both mitoROS and Nav1.5. PKCδ elevated mitoROS via enhancing the mitochondrial oxidative phosphorylation complex activities. PKCδ-mediated channel phosphorylation and mitoROS were both required to downregulate Nav1.5 and altered single channel conductance.

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“…For instance, an in vitro angiotensin-II-induced heart failure model reproduces the appearance observed in failing myocardia of two lossof-function Na V 1.5 channel isoforms produced by abnormal SCN5A splicing through a mechanism absent in species other than primates (Gao et al, 2011(Gao et al, , 2013. Such response contributes to the sodium current reduction in angiotensin-II-treated hPSC-CMs, mimicking pro-arrhythmic conditions in failing ventricles (Mathieu et al, 2016). Similarly, evolutionarily closer species display divergent transcriptomic responses to ischemiamimetic environments, with rhesus macaque monkey PSC-CMs failing to overlap results with hPSC-CMs at gene regulation level (Zhao et al, 2018), and chimpanzee PSC-CMs still diverging in regulation of critical genes tightly related to human ischemia/reperfusion pathogenesis (Ward and Gilad, 2019).…”

Section: Advantages and Limitationsmentioning

confidence: 84%

Beyond Family: Modeling Non-hereditary Heart Diseases With Human Pluripotent Stem Cell-Derived Cardiomyocytes

2020

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Non-genetic cardiac pathologies develop as an aftermath of extracellular stressconditions. Nevertheless, the response to pathological stimuli depends deeply on intracellular factors such as physiological state and complex genetic backgrounds. Without a thorough characterization of their in vitro phenotype, modeling of maladaptive hypertrophy, ischemia and reperfusion injury or diabetes in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) has been more challenging than hereditary diseases with defined molecular causes. In past years, greater insights into hPSC-CM in vitro physiology and advancements in technological solutions and culture protocols have generated cell types displaying stress-responsive phenotypes reminiscent of in vivo pathological events, unlocking their application as a reductionist model of human cardiomyocytes, if not the adult human myocardium. Here, we provide an overview of the available literature of pathology models for cardiac non-genetic conditions employing healthy (or asymptomatic) hPSC-CMs. In terms of numbers of published articles, these models are significantly lagging behind monogenic diseases, which misrepresents the incidence of heart disease causes in the human population.

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Reduction in Na+ current by angiotensin II is mediated by PKCα in mouse and human-induced pluripotent stem cell–derived cardiomyocytes

Cited by 16 publications

References 34 publications

Calcium‐dependent Nedd4‐2 upregulation mediates degradation of the cardiac sodium channel Nav1.5: implications for heart failure

Calcium‐dependent Nedd4‐2 upregulation mediates degradation of the cardiac sodium channel Nav1.5: implications for heart failure

Role of protein kinase C in metabolic regulation of the cardiac Na+ channel

Beyond Family: Modeling Non-hereditary Heart Diseases With Human Pluripotent Stem Cell-Derived Cardiomyocytes

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