Dysfunction of Diastolic [Ca2+] in Cardiomyocytes Isolated From Chagasic Patients

López, José R.; Espinosa, Raúl; Landazuru, Patricia; Linares, Nancy; Allen, Paul D.; Mijares, Alfrédo

doi:10.1016/j.rec.2011.01.008

Cited by 11 publications

(29 citation statements)

References 15 publications

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“…We found a 6% reduction in average Vm values in cardiomyocytes from FCI patients, and 11% in cardiomyocytes from FCII patients compared to control. These results confirm and extend our previous report demonstrating a diastolic Ca 2+ dysfunction in human cardiomyocytes from patients with Chagas' disease [23].…”

Section: [Ca 2+ ] D and [Na + ] D In Cardiomyocytes From Chagas' Patisupporting

confidence: 93%

“…We previously observed a significant increase in [Ca 2+ ] d in CC patients, which correlate directly with the extent of their cardiac dysfunction (NYHA class) regardless of gender [23]. Fig The partial depolarization observed in cardiomyocytes isolated from Chagas' patients correlates with the level of cardiac dysfunction determined by the NYHA classification.…”

Section: [Ca 2+ ] D and [Na + ] D In Cardiomyocytes From Chagas' Patimentioning

confidence: 70%

“…Earlier studies with non-human models [20][21][22] have shown there is a possible link between Chagas' infection and alteration in phospholipase-C/phosphoinositide signaling pathway. We recently demonstrated that cardiomyocytes isolated from Chagas patients have an intracellular Ca 2+ overload, which appears to be associated with changes in the inositol 1,4,5 trisphosphate (IP 3 ) signaling pathway [23]. IP 3 is a second messenger generated by hydrolysis of membrane lipid phosphatidylinositol 4,5-bisphosphate by phospholipase C in response to G protein-coupled receptor activation [24].…”

Section: Introductionmentioning

confidence: 99%

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Increases in [IP3]i aggravates diastolic [Ca2+] and contractile dysfunction in Chagas’ human cardiomyocytes

Mijares

Espinosa²,

Adams

et al. 2020

PLoS Negl Trop Dis

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Chagas cardiomyopathy is the most severe manifestation of human Chagas disease and represents the major cause of morbidity and mortality in Latin America. We previously demonstrated diastolic Ca 2+ alterations in cardiomyocytes isolated from Chagas' patients to different degrees of cardiac dysfunction. In addition, we have found a significant elevation of diastolic [Na + ] d in Chagas' cardiomyocytes (FCII>FCI) that was greater than control. Exposure of cardiomyocytes to agents that enhance inositol 1,4,5 trisphosphate (IP 3) generation or concentration like endothelin (ET-1) or bradykinin (BK), or membrane-permeant myoinositol 1,4,5-trisphosphate hexakis(butyryloxy-methyl) esters (IP 3 BM) caused an elevation in diastolic [Ca 2+ ] ([Ca 2+ ] d) that was always greater in cardiomyocytes from Chagas' than non-Chagas' subjects, and the magnitude of the [Ca 2+ ] d elevation in Chagas' cardiomyocytes was related to the degree of cardiac dysfunction. Incubation with xestospongin-C (Xest-C), a membrane-permeable selective blocker of the IP 3 receptors (IP 3 Rs), significantly reduced [Ca 2+ ] d in Chagas' cardiomyocytes but did not have a significant effect on non-Chagas' cells. The effects of ET-1, BK, and IP 3 BM on [Ca 2+ ] d were not modified by the removal of extracellular [Ca 2+ ] e. Furthermore, cardiomyocytes from Chagas' patients had a significant decrease in the sarcoplasmic reticulum (SR) Ca 2+ content compared to control (Control>F-CI>FCII), a higher intracellular IP 3 concentration ([IP 3 ] i) and markedly depressed contractile properties compared to control cardiomyocytes. These results provide additional and convincing support about the implications of IP 3 in the pathogenesis of Chagas cardiomyopathy in patients at different stages of chronic infection. Additionally, these findings open the door for novel therapeutic strategies oriented to improve cardiac function and quality of life of individuals suffering from chronic Chagas cardiomyopathy (CC).

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Section: [Ca 2+ ] D and [Na + ] D In Cardiomyocytes From Chagas' Patisupporting

confidence: 93%

Section: [Ca 2+ ] D and [Na + ] D In Cardiomyocytes From Chagas' Patimentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Increases in [IP3]i aggravates diastolic [Ca2+] and contractile dysfunction in Chagas’ human cardiomyocytes

Mijares

Espinosa²,

Adams

et al. 2020

PLoS Negl Trop Dis

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“…These data suggest that there might be another mechanism for the enhancement of the mitochondrial Ca 2+ clearance by a 1 -AR-Pyk2 signaling in addition to the MCU oligomerization. In cardiac cells, a 1 -ARS increases the resting (diastolic) [Ca 2+ ] c levels (34,44,61) and/or spontaneous Ca 2+ release (45) although its effect to peak [Ca 2+ ] c is relatively small. Therefore, after 15 min of Phe stimulation, a 1 -AR-AR-Pyk2 signaling may change the Ca 2+ sensitivity of MCU through channel tyrosine phosphorylation and mitochondria might accumulate Ca 2+ more efficiently under the enhancement of spontaneous Ca 2+ releases from ER/SR and/or the increase of resting [Ca 2+ ] c levels by Phe.…”

Section: -Ar-pyk2 Signaling Triggers Mso Generation and Cell Death Inmentioning

confidence: 99%

Adrenergic Signaling Regulates Mitochondrial Ca²⁺ Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca²⁺ Uniporter

O‐Uchi

Jhun

et al. 2014

Antioxidants & Redox Signaling

109

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Aims: Mitochondrial Ca 2+ homeostasis is crucial for balancing cell survival and death. The recent discovery of the molecular identity of the mitochondrial Ca 2+ uniporter pore (MCU) opens new possibilities for applying genetic approaches to study mitochondrial Ca 2+ regulation in various cell types, including cardiac myocytes. Basal tyrosine phosphorylation of MCU was reported from mass spectroscopy of human and mouse tissues, but the signaling pathways that regulate mitochondrial Ca 2+ entry through posttranslational modifications of MCU are completely unknown. Therefore, we investigated a 1 -adrenergic-mediated signal transduction of MCU posttranslational modification and function in cardiac cells. Results: a 1 -adrenoceptor (a 1 -AR) signaling translocated activated proline-rich tyrosine kinase 2 (Pyk2) from the cytosol to mitochondrial matrix and accelerates mitochondrial Ca 2+ uptake via Pyk2-dependent MCU phosphorylation and tetrametric MCU channel pore formation. Moreover, we found that a 1 -AR stimulation increases reactive oxygen species production at mitochondria, mitochondrial permeability transition pore activity, and initiates apoptotic signaling via Pyk2-dependent MCU activation and mitochondrial Ca 2+ overload. Innovation: Our data indicate that inhibition of a 1 -AR-Pyk2-MCU signaling represents a potential novel therapeutic target to limit or prevent mitochondrial Ca 2+ overload, oxidative stress, mitochondrial injury, and myocardial death during pathophysiological conditions, where chronic adrenergic stimulation is present. Conclusion: The a 1 -AR-Pyk2-dependent tyrosine phosphorylation of the MCU regulates mitochondrial Ca 2+ entry and apoptosis in cardiac cells. Antioxid. Redox Signal. 21, 863-879.

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“…Interestingly, the existence of calcium overload in the ventricular myocytes of chagasic patients was recently reported (17). It is well known that increases in the intracellular calcium levels are responsible for the extension of the plateau phase of the cardiac action potential.…”

Section: Discussionmentioning

confidence: 98%

Induction of chagasic-like arrhythmias in the isolated beating hearts of healthy rats perfused with Trypanosoma cruzi-conditioned medium

Rodriguez-Angulo¹,

Toro-Mendoza²,

Marques³

et al. 2013

Braz. J. Med. Biol. Res.

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Chagas' myocardiopathy, caused by the intracellular protozoan Trypanosoma cruzi, is characterized by microvascular alterations, heart failure and arrhythmias. Ischemia and arrythmogenesis have been attributed to proteins shed by the parasite, although this has not been fully demonstrated. The aim of the present investigation was to study the effect of substances shed by T. cruzi on ischemia/reperfusion-induced arrhythmias. We performed a triple ischemia-reperfusion (I/R) protocol whereby the isolated beating rat hearts were perfused with either Vero-control or Vero T. cruzi-infected conditioned medium during the different stages of ischemia and subsequently reperfused with Tyrode's solution. ECG and heart rate were recorded during the entire experiment. We observed that triple I/R-induced bradycardia was associated with the generation of auricular-ventricular blockade during ischemia and non-sustained nodal and ventricular tachycardia during reperfusion. Interestingly, perfusion with Vero-infected medium produced a delay in the reperfusion-induced recovery of heart rate, increased the frequency of tachycardic events and induced ventricular fibrillation. These results suggest that the presence of parasite-shed substances in conditioned media enhances the arrhythmogenic effects that occur during the I/R protocol.

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Dysfunction of Diastolic [Ca2+] in Cardiomyocytes Isolated From Chagasic Patients

Cited by 11 publications

References 15 publications

Increases in [IP3]i aggravates diastolic [Ca2+] and contractile dysfunction in Chagas’ human cardiomyocytes

Increases in [IP3]i aggravates diastolic [Ca2+] and contractile dysfunction in Chagas’ human cardiomyocytes

Adrenergic Signaling Regulates Mitochondrial Ca²⁺ Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca²⁺ Uniporter

Induction of chagasic-like arrhythmias in the isolated beating hearts of healthy rats perfused with Trypanosoma cruzi-conditioned medium

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Dysfunction of Diastolic [Ca2+] in Cardiomyocytes Isolated From Chagasic Patients

Cited by 11 publications

References 15 publications

Increases in [IP3]i aggravates diastolic [Ca2+] and contractile dysfunction in Chagas’ human cardiomyocytes

Increases in [IP3]i aggravates diastolic [Ca2+] and contractile dysfunction in Chagas’ human cardiomyocytes

Adrenergic Signaling Regulates Mitochondrial Ca2+ Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca2+ Uniporter

Induction of chagasic-like arrhythmias in the isolated beating hearts of healthy rats perfused with Trypanosoma cruzi-conditioned medium

Contact Info

Product

Resources

About

Adrenergic Signaling Regulates Mitochondrial Ca²⁺ Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca²⁺ Uniporter