Digoxin and ouabain induce the efflux of cholesterol via liver X receptor signalling and the synthesis of ATP in cardiomyocytes

Campia, Ivana; Sala, Valentina; Kopecka, Joanna; Leo, Christian; Mitro, Nico; Costamagna, Costanzo; Caruso, Donatella; Pescarmona, Gianpiero; Crepaldi, Tiziana; Ghigo, Dario; Bosìa, Amalia; Riganti, Chiara

doi:10.1042/bj20120200

Cited by 28 publications

(29 citation statements)

References 39 publications

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“…The ATP reduction induced by ouabain was much less than that induced by cyanide and 2-deoxyglucosein, so the ATP loss observed in this experiment was likely caused by the increase of ATP consumption rather than the impairment of mitochondrial ATP synthesis. On the contrary, it has been shown that ouabain directly enhanced the rate of electron transport chain and the synthesis of ATP in cardiomyocytes via increasing the synthesis of ubiquinone [7]. These contradictory results might be due to differences in experimental conditions, animal species or tissue variations.…”

Section: Discussionmentioning

confidence: 98%

“…In previous animal and clinical studies, the arrhythmogenic effects of glycosides have been mainly attributed to NKA inhibition-induced Ca 2+ overload and associated abnormal RyR Ca 2+ release [2], [5], [7], [8], [44]. More recently, studies by Liu et al suggested that mitochondrial dysfunction, particularly ouabain-induced ROS production, might also contribute to the arrhythmogenic effect of glycosides [1].…”

Section: Discussionmentioning

confidence: 99%

“…However, recently the use of glycoside treatment in HF patients has been largely supplanted by other drugs (e.g., angiotensin-converting enzyme (ACE) inhibitors, β-blockers and aldosterone antagonists) and cardiac resynchronization therapies [5], [6]. The diminished use of glycosides in the clinic was partially due to their well-known side effects such as cardiac arrhythmias, gastrointestinal symptoms, and central nervous system abnormalities [2], [5], [7], [8]. Whereas the proarrhythmic effect of glycosides largely confines their clinic applications, the detailed underlying molecular mechanisms are not completely understood.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibiting Na+/K+ ATPase Can Impair Mitochondrial Energetics and Induce Abnormal Ca2+ Cycling and Automaticity in Guinea Pig Cardiomyocytes

Pogwizd

Prabhu

et al. 2014

PLoS ONE

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Cardiac glycosides have been used for the treatment of heart failure because of their capabilities of inhibiting Na+/K+ ATPase (NKA), which raises [Na+]i and attenuates Ca2+ extrusion via the Na+/Ca2+ exchanger (NCX), causing [Ca2+]i elevation. The resulting [Ca2+]i accumulation further enhances Ca2+-induced Ca2+ release, generating the positive inotropic effect. However, cardiac glycosides have some toxic and side effects such as arrhythmogenesis, confining their extensive clinical applications. The mechanisms underlying the proarrhythmic effect of glycosides are not fully understood. Here we investigated the mechanisms by which glycosides could cause cardiac arrhythmias via impairing mitochondrial energetics using an integrative computational cardiomyocyte model. In the simulations, the effect of glycosides was mimicked by blocking NKA activity. Results showed that inhibiting NKA not only impaired mitochondrial Ca2+ retention (thus suppressed reactive oxygen species (ROS) scavenging) but also enhanced oxidative phosphorylation (thus increased ROS production) during the transition of increasing workload, causing oxidative stress. Moreover, concurrent blocking of mitochondrial Na+/Ca2+ exchanger, but not enhancing of Ca2+ uniporter, alleviated the adverse effects of NKA inhibition. Intriguingly, NKA inhibition elicited Ca2+ transient and action potential alternans under more stressed conditions such as severe ATP depletion, augmenting its proarrhythmic effect. This computational study provides new insights into the mechanisms underlying cardiac glycoside-induced arrhythmogenesis. The findings suggest that targeting both ion handling and mitochondria could be a very promising strategy to develop new glycoside-based therapies in the treatment of heart failure.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibiting Na+/K+ ATPase Can Impair Mitochondrial Energetics and Induce Abnormal Ca2+ Cycling and Automaticity in Guinea Pig Cardiomyocytes

Pogwizd

Prabhu

et al. 2014

PLoS ONE

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“…Chromatin immunoprecipitation (ChIP) samples were prepared as previously reported using a ChIP‐tested anti‐c‐myc antibody (mouse clone 9E11; Abcam, Cambridge, UK). The putative c‐Myc binding site on ABCB5 promoter was validated with the Matinspector software (https://www.genomatix.de/matinspector.html).…”

Section: Methodsmentioning

confidence: 99%

Wnt/IL‐1β/IL‐8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5

Milosevic

Kopecka

Salaroglio

et al. 2019

Intl Journal of Cancer

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Malignant pleural mesothelioma (MPM) is a tumor with high chemoresistance and poor prognosis. MPM‐initiating cells (ICs) are known to be drug resistant, but it is unknown if and how stemness‐related pathways determine chemoresistance. Moreover, there are no predictive markers of IC‐associated chemoresistance. Aim of this work is to clarify if and by which mechanisms the chemoresistant phenotype of MPM IC was due to specific stemness‐related pathways. We generated MPM IC from primary MPM samples and compared the gene expression and chemo‐sensitivity profile of IC and differentiated/adherent cells (AC) of the same patient. Compared to AC, IC had upregulated the drug efflux transporter ABCB5 that determined resistance to cisplatin and pemetrexed. ABCB5‐knocked‐out (KO) IC clones were resensitized to the drugs in vitro and in patient‐derived xenografts. ABCB5 was transcriptionally activated by the Wnt/GSK3β/β‐catenin/c‐myc axis that also increased IL‐8 and IL‐1β production. IL‐8 and IL‐1β‐KO IC clones reduced the c‐myc‐driven transcription of ABCB5 and reacquired chemosensitivity. ABCB5‐KO clones had lower IL‐8 and IL‐1β secretion, and c‐myc transcriptional activity, suggesting that either Wnt/GSK3β/β‐catenin and IL‐8/IL‐1β signaling drive c‐myc‐mediated transcription of ABCB5. ABCB5 correlated with lower time‐to‐progression and overall survival in MPM patients treated with cisplatin and pemetrexed. Our work identified multiple autocrine loops linking stemness pathways and resistance to cisplatin and pemetrexed in MPM IC. ABCB5 may represent a new target to chemosensitize MPM IC and a potential biomarker to predict the response to the first‐line chemotherapy in MPM patients.

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“…ChIP samples were prepared as described by Campia et al 49,. using a ChIP-tested anti-LXRα antibody (61175, Active Motif, dilution 1/50).…”

Section: Methodsmentioning

confidence: 99%

The ATP-binding cassette transporter A1 regulates phosphoantigen release and Vγ9Vδ2 T cell activation by dendritic cells

et al. 2017

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Vγ9Vδ2 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen-presenting cells. IPP is released in the extracellular microenvironment via unknown mechanisms. Here we show that the ATP-binding cassette transporter A1 (ABCA1) mediates extracellular IPP release from dendritic cells (DC) in cooperation with apolipoprotein A-I (apoA-I) and butyrophilin-3A1. IPP concentrations in the supernatants are sufficient to induce Vγ9Vδ2 T cell proliferation after DC mevalonate pathway inhibition with zoledronic acid (ZA). ZA treatment increases ABCA1 and apoA-I expression via IPP-dependent LXRα nuclear translocation and PI3K/Akt/mTOR pathway inhibition. These results close the mechanistic gap in our understanding of extracellular IPP release from DC and provide a framework to fine-tune Vγ9Vδ2 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation.

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Digoxin and ouabain induce the efflux of cholesterol via liver X receptor signalling and the synthesis of ATP in cardiomyocytes

Cited by 28 publications

References 39 publications

Inhibiting Na+/K+ ATPase Can Impair Mitochondrial Energetics and Induce Abnormal Ca2+ Cycling and Automaticity in Guinea Pig Cardiomyocytes

Inhibiting Na+/K+ ATPase Can Impair Mitochondrial Energetics and Induce Abnormal Ca2+ Cycling and Automaticity in Guinea Pig Cardiomyocytes

Wnt/IL‐1β/IL‐8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5

The ATP-binding cassette transporter A1 regulates phosphoantigen release and Vγ9Vδ2 T cell activation by dendritic cells

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