Cellular Mechanisms Underlying the Low Cardiotoxicity of Istaroxime
Background: Istaroxime is an inhibitor of Na⁺/K⁺ ATPase with proven efficacy to increase cardiac contractility and to accelerate relaxation attributable to a relief in phospholamban-dependent inhibition of the sarcoplasmic reticulum Ca²⁺ ATPase. We have previously shown that pharmacologic Na⁺/K⁺ ATP...
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| Autores principales: | , , , , |
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| Formato: | Articulo |
| Lenguaje: | Inglés |
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2021
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| Acceso en línea: | http://sedici.unlp.edu.ar/handle/10915/136866 |
| Aporte de: |
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I19-R120-10915-136866 |
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| record_format |
dspace |
| institution |
Universidad Nacional de La Plata |
| institution_str |
I-19 |
| repository_str |
R-120 |
| collection |
SEDICI (UNLP) |
| language |
Inglés |
| topic |
Medicina Ca2+/calmodulin-dependent kinase II cardiotoxicity digitalis and apoptosis istaroxime |
| spellingShingle |
Medicina Ca2+/calmodulin-dependent kinase II cardiotoxicity digitalis and apoptosis istaroxime Racioppi, María Florencia Burgos Migone, Juan Ignacio Morell, Malena Gonano, Luis Alberto Vila Petroff, Martín Gerardo Cellular Mechanisms Underlying the Low Cardiotoxicity of Istaroxime |
| topic_facet |
Medicina Ca2+/calmodulin-dependent kinase II cardiotoxicity digitalis and apoptosis istaroxime |
| description |
Background: Istaroxime is an inhibitor of Na⁺/K⁺ ATPase with proven efficacy to increase cardiac contractility and to accelerate relaxation attributable to a relief in phospholamban-dependent inhibition of the sarcoplasmic reticulum Ca²⁺ ATPase. We have previously shown that pharmacologic Na⁺/K⁺ ATPase inhibition promotes calcium/calmodulin-dependent kinase II activation, which mediates both cardiomyocyte death and arrhythmias. Here, we aim to compare the cardiotoxic effects promoted by classic pharmacologic Na⁺/K⁺ ATPase inhibition versus istaroxime.
Methods and results: Ventricular cardiomyocytes were treated with ouabain or istaroxime at previously tested equi-inotropic concentrations to compare their impact on cell viability, apoptosis, and calcium/calmodulin-dependent kinase II activation. In contrast to ouabain, istaroxime neither promoted calcium/calmodulin-dependent kinase II activation nor cardiomyocyte death. In addition, we explored the differential behavior promoted by ouabain and istaroxime on spontaneous diastolic Ca²⁺ release. In rat cardiomyocytes, istaroxime did not significantly increase Ca²⁺ spark and wave frequency but increased the proportion of aborted Ca²⁺ waves. Further insight was provided by studying cardiomyocytes from mice that do not express phospholamban. In this model, the lower Ca²⁺ wave incidence observed with istaroxime remains present, suggesting that istaroxime-dependent relief on phospholamban-dependent sarcoplasmic reticulum Ca²⁺ ATPase 2A inhibition is not the unique mechanism underlying the low arrhythmogenic profile of this drug.
Conclusions: Our results indicate that, different from ouabain, istaroxime can reach a significant inotropic effect without leading to calcium/calmodulin-dependent kinase II–dependent cardiomyocyte death. Additionally, we provide novel insights regarding the low arrhythmogenic impact of istaroxime on cardiac Ca²⁺ handling. |
| format |
Articulo Articulo |
| author |
Racioppi, María Florencia Burgos Migone, Juan Ignacio Morell, Malena Gonano, Luis Alberto Vila Petroff, Martín Gerardo |
| author_facet |
Racioppi, María Florencia Burgos Migone, Juan Ignacio Morell, Malena Gonano, Luis Alberto Vila Petroff, Martín Gerardo |
| author_sort |
Racioppi, María Florencia |
| title |
Cellular Mechanisms Underlying the Low Cardiotoxicity of Istaroxime |
| title_short |
Cellular Mechanisms Underlying the Low Cardiotoxicity of Istaroxime |
| title_full |
Cellular Mechanisms Underlying the Low Cardiotoxicity of Istaroxime |
| title_fullStr |
Cellular Mechanisms Underlying the Low Cardiotoxicity of Istaroxime |
| title_full_unstemmed |
Cellular Mechanisms Underlying the Low Cardiotoxicity of Istaroxime |
| title_sort |
cellular mechanisms underlying the low cardiotoxicity of istaroxime |
| publishDate |
2021 |
| url |
http://sedici.unlp.edu.ar/handle/10915/136866 |
| work_keys_str_mv |
AT racioppimariaflorencia cellularmechanismsunderlyingthelowcardiotoxicityofistaroxime AT burgosmigonejuanignacio cellularmechanismsunderlyingthelowcardiotoxicityofistaroxime AT morellmalena cellularmechanismsunderlyingthelowcardiotoxicityofistaroxime AT gonanoluisalberto cellularmechanismsunderlyingthelowcardiotoxicityofistaroxime AT vilapetroffmartingerardo cellularmechanismsunderlyingthelowcardiotoxicityofistaroxime |
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Repositorios |
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1764820457442246657 |