The STIM1 inhibitor ML9 disrupts basal autophagy in cardiomyocytes by decreasing lysosome content
| Autor: | David Mondaca-Ruff, Rodrigo Troncoso, Soni Shaikh, Mario Chiong, Sergio Lavandero, Valentina Parra, Lorena García |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Programmed cell death Necrosis Apoptosis Toxicology 03 medical and health sciences Lysosome medicine Extracellular Autophagy Animals Myocytes Cardiac Stromal Interaction Molecule 1 Cells Cultured Cell Death Chemistry General Medicine Azepines medicine.disease Cell biology Mitochondria Rats 030104 developmental biology medicine.anatomical_structure Animals Newborn medicine.symptom Lysosomes Reactive Oxygen Species Reperfusion injury Intracellular |
| Zdroj: | Toxicology in vitro : an international journal published in association with BIBRA. 48 |
| ISSN: | 1879-3177 |
| Popis: | Stromal-interaction molecule 1 (STIM1)-mediated store-operated Ca2+ entry (SOCE) plays a key role in mediating cardiomyocyte hypertrophy, both in vitro and in vivo. Moreover, there is growing support for the contribution of SOCE to the Ca2+ overload associated with ischemia/reperfusion injury. Therefore, STIM1 inhibition is proposed as a novel target for controlling both hypertrophy and ischemia/reperfusion-induced Ca2+ overload. Our aim was to evaluate the effect of ML9, a STIM1 inhibitor, on cardiomyocyte viability. ML9 was found to induce cell death in cultured neonatal rat cardiomyocytes. Caspase-3 activation, apoptotic index and release of the necrosis marker lactate dehydrogenase to the extracellular medium were evaluated. ML9-induced cardiomyocyte death was not associated with increased intracellular ROS or decreased ATP levels. Moreover, treatment with ML9 significantly increased levels of the autophagy marker LC3-II, without altering Beclin1 or p62 protein levels. However, treatment with ML9 followed by bafilomycin-A1 did not produce further increases in LC3-II content. Furthermore, treatment with ML9 resulted in decreased LysoTracker® Green staining. Collectively, these data suggest that ML9-induced cardiomyocyte death is triggered by a ML9-dependent disruption of autophagic flux due to lysosomal dysfunction. |
| Databáze: | OpenAIRE |
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