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Hyperosmotic stress promotes endoplasmic reticulum stress-dependent apoptosis in adult rat cardiac myocytes

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Abstract

In different pathological situations, cardiac cells undergo hyperosmotic stress and cell shrinkage. This change in cellular volume has been associated with contractile dysfunction and cell death. However, the intracellular mechanisms involved in hyperosmotic stress-induced cell death have not been investigated in depth in adult cardiac myocytes. Given that osmotic stress has been shown to promote endoplasmic reticulum stress (ERS), a recognized trigger for apoptosis, we examined whether hyperosmotic stress triggers ERS in adult cardiac myocytes and if so whether this mechanism mediates hyperosmotic stress-induced cell death. Adult rat cardiomyocytes cultured overnight in a hypertonic solution (HS) containing mannitol as the osmolite, showed increased expression of ERS markers, GRP78, CHOP and cleaved-Caspase-12, compared with myocytes in isotonic solution (IS), suggesting that hyperosmotic stress induces ERS. In addition, HS significantly reduced cell viability and increased TUNEL staining and the expression of active Caspase-3, indicative of apoptosis. These effects were prevented with the addition of the ERS inhibitor, 4-PBA, indicating that hyperosmotic stress-induced apoptosis is mediated by ERS. Hyperosmotic stress-induced apoptosis was also prevented when cells were cultured in the presence of a Ca2+-chelating agent (EGTA) or the CaMKII inhibitor (KN93), suggesting that hyperosmotic stress-induced ERS is mediated by a Ca2+ and CaMKII-dependent mechanism. Similar results were observed when hyperosmotic stress was induced using glucose as the osmolite. We conclude that hyperosmotic stress promotes ERS by a CaMKII-dependent mechanism leading to apoptosis of adult cardiomyocytes. More importantly, we demonstrate that hyperosmotic stress-triggered ERS contributes to hyperglycemia-induced cell death.

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Acknowledgements

The technical support of Mónica Rando and Omar Castillo are gratefully acknowledged.

Funding

This study was supported by Grants PICT 1678 from Fondo para la Investigación Científica y Tecnológica (FONCyT) and PIP 0270 from El Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) to Martín Vila Petroff.

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  1. Juan Ignacio Burgos and Malena Morell have Contributed equally to this work.

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  1. Centro de Investigaciones Cardiovasculares, CONICET La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina

    Juan Ignacio Burgos, Malena Morell, Juan Ignacio E. Mariángelo & Martin Vila Petroff

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  1. Juan Ignacio Burgos
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Burgos, J.I., Morell, M., Mariángelo, J.I.E. et al. Hyperosmotic stress promotes endoplasmic reticulum stress-dependent apoptosis in adult rat cardiac myocytes. Apoptosis 24, 785–797 (2019). https://doi.org/10.1007/s10495-019-01558-4

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