2. Academic Validation
  3. The STIM1 inhibitor ML9 disrupts basal autophagy in cardiomyocytes by decreasing lysosome content

The STIM1 inhibitor ML9 disrupts basal autophagy in cardiomyocytes by decreasing lysosome content

  • Toxicol In Vitro. 2018 Apr;48:121-127. doi: 10.1016/j.tiv.2018.01.005.
S Shaikh 1,  R Troncoso 2,  D Mondaca-Ruff 1,  V Parra 1,  L Garcia 1,  M Chiong 3,  S Lavandero 4
Affiliations

Affiliations

  • 1 Advanced Center for Chronic Disease (ACCDiS) & Center of Exercise, Metabolism and Cancer (CEMC), Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine, University of Chile, Santiago, Chile.
  • 2 Advanced Center for Chronic Disease (ACCDiS) & Center of Exercise, Metabolism and Cancer (CEMC), Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine, University of Chile, Santiago, Chile; Institute for Nutrition and Food Technology (INTA), University of Chile, Chile.
  • 3 Advanced Center for Chronic Disease (ACCDiS) & Center of Exercise, Metabolism and Cancer (CEMC), Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine, University of Chile, Santiago, Chile. Electronic address: mchiong@uchile.cl.
  • 4 Advanced Center for Chronic Disease (ACCDiS) & Center of Exercise, Metabolism and Cancer (CEMC), Faculty of Chemical & Pharmaceutical Sciences & Faculty of Medicine, University of Chile, Santiago, Chile; Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: slavander@uchile.cl.
PMID: 29337250 DOI: 10.1016/j.tiv.2018.01.005
Abstract

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.

Keywords

Autophagy; Cardiomyocytes; Cell death; LC3; Lysosomes; ML9.

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