Pharmacologic inhibition of the mitochondrial Na+/Ca2+ exchanger protects against ventricular arrhythmias in a porcine model of ischemia-reperfusion

Sventzouri, Stefania; Nanas, Ioannis; Vakrou, Styliani; Kapelios, Chris J.; Sousonis, Vasilios; Sfakianaki, Titika; Papalois, Αpostolos; Manolis, Antonis S.; Nanas, John N.; Malliaras, Konstantinos

doi:10.1016/j.hjc.2017.12.009

Cited by 9 publications

(7 citation statements)

References 32 publications

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“…Ventricular tachycardia was prevented in vivo, and similar results were found in iPSC-derived human cardiomyocytes (Schweitzer et al, 2017). Furthermore, enhancing mitochondrial Ca 2+ content using the mNCX inhibitor CGP-37157 suppressed ventricular arrhythmias, lowered the depression of the J point during ischemia, and expedited ST-segment resolution after reperfusion in a porcine model of I/R (Sventzouri et al, 2018). Likewise, enhancing mitochondrial Ca 2+ transport using the mCU activator spermine in isolated rabbit atrial cardiomyocytes undergoing a tachypacing protocol to induce AF demonstrated a protective effect against Ca 2+ transient alternans.…”

Section: Regulation Of Mitochondrial Ca 2+ Transportsupporting

confidence: 58%

Mitochondrial and Sarcoplasmic Reticulum Interconnection in Cardiac Arrhythmia

Salazar-Ramírez

Ramos-Mondragón

García‐Rivas

2021

Front. Cell Dev. Biol.

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Ca2+ plays a pivotal role in mitochondrial energy production, contraction, and apoptosis. Mitochondrial Ca2+-targeted fluorescent probes have demonstrated that mitochondria Ca2+ transients are synchronized with Ca2+ fluxes occurring in the sarcoplasmic reticulum (SR). The presence of specialized proteins tethering SR to mitochondria ensures the local Ca2+ flux between these organelles. Furthermore, communication between SR and mitochondria impacts their functionality in a bidirectional manner. Mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniplex is essential for ATP production and controlled reactive oxygen species levels for proper cellular signaling. Conversely, mitochondrial ATP ensures the proper functioning of SR Ca2+-handling proteins, which ensures that mitochondria receive an adequate supply of Ca2+. Recent evidence suggests that altered SR Ca2+ proteins, such as ryanodine receptors and the sarco/endoplasmic reticulum Ca2+ ATPase pump, play an important role in maintaining proper cardiac membrane excitability, which may be initiated and potentiated when mitochondria are dysfunctional. This recognized mitochondrial role offers the opportunity to develop new therapeutic approaches aimed at preventing cardiac arrhythmias in cardiac disease.

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Section: Regulation Of Mitochondrial Ca 2+ Transportsupporting

confidence: 58%

Mitochondrial and Sarcoplasmic Reticulum Interconnection in Cardiac Arrhythmia

Salazar-Ramírez

Ramos-Mondragón

García‐Rivas

2021

Front. Cell Dev. Biol.

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“…Finally, excessive mitochondrial Ca ++ efflux via mitochondrial NCX has been shown to increase oxidative stress and arrhythmias leading to SCD 192 . Pharmacologic inhibition of NCX with CGP‐37157 attenuates the incidence of ventricular arrhythmias, supporting a role of mitochondrial Ca ++ ‐related signaling in arrhythmogenicity 193 …”

Section: Targeting the Mitochondriamentioning

confidence: 98%

“…192 Pharmacologic inhibition of NCX with CGP-37157 attenuates the incidence of ventricular arrhythmias, supporting a role of mitochondrial Ca ++ -related signaling in arrhythmogenicity. 193 Several K + channels have been identified in the inner membrane of the mitochondria, such as the ATPdependent (mitoK ATP ), the voltage-gated Kv1.3 (mitoKv1.3), the calcium-activated (mitoBKCa) and the two-pore domain TASK-3 (mitoTASK) potassium channels. 194 They affect the integrity of the inner membrane and thus regulate mitochondrial functions, such as energy-transducing processes and ROS production.…”

Section: Mitochondrial Ion Channelsmentioning

confidence: 99%

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Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications

Manolis¹,

Manolis

et al. 2020

Medicinal Research Reviews

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Mitochondria provide energy to the cell during aerobic respiration by supplying ~95% of the adenosine triphosphate (ATP) molecules via oxidative phosphorylation. These organelles have various other functions, all carried out by numerous proteins, with the majority of them being encoded by nuclear DNA (nDNA). Mitochondria occupy ~1/3 of the volume of myocardial cells in adults, and function at levels of high‐efficiency to promptly meet the energy requirements of the myocardial contractile units. Mitochondria have their own DNA (mtDNA), which contains 37 genes and is maternally inherited. Over the last several years, a variety of functions of these organelles have been discovered and this has led to a growing interest in their involvement in various diseases, including cardiovascular (CV) diseases. Mitochondrial dysfunction relates to the status where mitochondria cannot meet the demands of a cell for ATP and there is an enhanced formation of reactive‐oxygen species. This dysfunction may occur as a result of mtDNA and/or nDNA mutations, but also as a response to aging and various disease and environmental stresses, leading to the development of cardiomyopathies and other CV diseases. Designing mitochondria‐targeted therapeutic strategies aiming to maintain or restore mitochondrial function has been a great challenge as a result of variable responses according to the etiology of the disorder. There have been several preclinical data on such therapies, but clinical studies are scarce. A major challenge relates to the techniques needed to eclectically deliver the therapeutic agents to cardiac tissues and to damaged mitochondria for successful clinical outcomes. All these issues and progress made over the last several years are herein reviewed.

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“…In I/R, excessive Ca 2+ entry may be related to the Na + /Ca 2+ exchanger (NCX), and ablation of the NCX may protect against myocardial I/R injury [39]. Additionally, inhibition of the NCX may reduce the QT interval and arrhythmia [40, 41]. Previous studies showed that TLR4 activation may increase the expression of NCX, reduce the transient outward potassium current (Ito), and prolong the APD and QT interval [42, 43].…”

Section: Discussionmentioning

confidence: 99%

Daphnetin Preconditioning Decreases Cardiac Injury and Susceptibility to Ventricular Arrhythmia following Ischaemia-Reperfusion through the TLR4/MyD88/NF-Κb Signalling Pathway

et al. 2021

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Background/Aims: Daphnetin (7,8-dihydroxycoumarin, DAP) exhibits various bioactivities, such as anti-inflammatory and antioxidant activities. However, the role of DAP in myocardial ischaemia/reperfusion (I/R) injury and I/R-related arrhythmia is still uncertain. This study aimed to investigate the mechanisms underlying the effects of DAP on myocardial I/R injury and electrophysiological properties in vivo and in vitro. Methods: Myocardial infarct size was measured by triphenyltetrazolium chloride staining. Cardiac function was assessed by echocardiographic and haemodynamic analyses. The levels of creatine kinase-MB, lactate dehydrogenase, malondialdehyde, superoxide dismutase, interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α) were detected using commercial kits. Apoptosis was measured by terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labelling staining and flow cytometry. The viability of H9c2 cells was determined by the Cell Counting Kit-8 assay. In vitro, the levels of IL-6 and TNF-α were measured by quantitative PCR. The expression levels of proteins associated with apoptosis, inflammation, and the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor kappa B (TLR4/MyD88/NF-κB) signalling pathway were detected by Western blot analysis. The RR, PR, QRS, and QTc intervals were assessed by surface ECG. The 90% action potential duration (APD90), threshold of APD alternans, and ventricular tachycardia inducibility were measured by the Langendorff perfusion technique. Results: DAP preconditioning decreased myocardial I/R injury and hypoxia/reoxygenation (H/R) injury in cells. DAP preconditioning improved cardiac function after myocardial I/R injury. DAP preconditioning also suppressed apoptosis, attenuated oxidative stress, and inhibited inflammatory responses in vivo and in vitro. Furthermore, DAP preconditioning decreased the susceptibility to ventricular arrhythmia after myocardial I/R. Finally, DAP preconditioning inhibited the expression of TLR4, MyD88, and phosphorylated NF-κB (p-NF-κB)/P65 in mice subjected to I/R and cells subjected to H/R. Conclusions: DAP preconditioning protected against myocardial I/R injury and decreased susceptibility to ventricular arrhythmia by inhibiting the TLR4/MyD88/NF-κB signalling pathway.

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Pharmacologic inhibition of the mitochondrial Na+/Ca2+ exchanger protects against ventricular arrhythmias in a porcine model of ischemia-reperfusion

Cited by 9 publications

References 32 publications

Mitochondrial and Sarcoplasmic Reticulum Interconnection in Cardiac Arrhythmia

Mitochondrial and Sarcoplasmic Reticulum Interconnection in Cardiac Arrhythmia

Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications

Daphnetin Preconditioning Decreases Cardiac Injury and Susceptibility to Ventricular Arrhythmia following Ischaemia-Reperfusion through the TLR4/MyD88/NF-Κb Signalling Pathway

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