Journal
APOPTOSIS
Volume 15, Issue 8, Pages 887-903Publisher
SPRINGER
DOI: 10.1007/s10495-010-0505-9
Keywords
Cardiomyocyte; Hyperosmotic stress; Sorbitol; Calcium; Metabolic collapse; CREB
Categories
Funding
- FONDAP (Fondo de Areas Prioritarias, Fondo Nacional de Desarrollo Cientifico y Tecnologico, CONICYT, Chile) [15010006]
- ECOS-CONICTY [C04B03, C08S01]
- FONDECYT [3070043]
- CONICYT, Chile
Ask authors/readers for more resources
Hyperosmotic stress promotes rapid and pronounced apoptosis in cultured cardiomyocytes. Here, we investigated if Ca2+ signals contribute to this response. Exposure of cardiomyocytes to sorbitol [600 mosmol (kg water)(-1)] elicited large and oscillatory intracellular Ca2+ concentration increases. These Ca2+ signals were inhibited by nifedipine, Cd2+, U73122, xestospongin C and ryanodine, suggesting contributions from both Ca2+ influx through voltage dependent L-type Ca2+ channels plus Ca2+ release from intracellular stores mediated by IP3 receptors and ryanodine receptors. Hyperosmotic stress also increased mitochondrial Ca2+ levels, promoted mitochondrial depolarization, reduced intracellular ATP content, and activated the transcriptional factor cyclic AMP responsive element binding protein (CREB), determined by increased CREB phosphorylation and electrophoretic mobility shift assays. Incubation with 1 mM EGTA to decrease extracellular [Ca2+] prevented cardiomyocyte apoptosis induced by hyperosmotic stress, while overexpression of an adenoviral dominant negative form of CREB abolished the cardioprotection provided by 1 mM EGTA. These results suggest that hyperosmotic stress induced by sorbitol, by increasing Ca2+ influx and raising intracellular Ca2+ concentration, activates Ca2+ release from stores and causes cell death through mitochondrial function collapse. In addition, the present results suggest that the Ca2+ increase induced by hyperosmotic stress promotes cell survival by recruiting CREB-mediated signaling. Thus, the fate of cardiomyocytes under hyperosmotic stress will depend on the balance between Ca2+-induced survival and death pathways.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available