Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Bosche, B; Schäfer, M; Graf, R; Härtel, FV; Schäfer, U; Noll, T.
Lithium prevents early cytosolic calcium increase and secondary injurious calcium overload in glycolytically inhibited endothelial cells.
Biochem Biophys Res Commun. 2013; 434(2):268-272
Doi: 10.1016/j.bbrc.2013.03.047
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Schäfer Ute
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- Abstract:
- Cytosolic free calcium concentration ([Ca(2+)]i) is a central signalling element for the maintenance of endothelial barrier function. Under physiological conditions, it is controlled within narrow limits. Metabolic inhibition during ischemia/reperfusion, however, induces [Ca(2+)]i overload, which results in barrier failure. In a model of cultured porcine aortic endothelial monolayers (EC), we addressed the question of whether [Ca(2+)]i overload can be prevented by lithium treatment. [Ca(2+)]i and ATP were analysed using Fura-2 and HPLC, respectively. The combined inhibition of glycolytic and mitochondrial ATP synthesis by 2-desoxy-d-glucose (5mM; 2-DG) plus sodium cyanide (5mM; NaCN) caused a significant decrease in cellular ATP content (14±1 nmol/mg protein vs. 18±1 nmol/mg protein in the control, n=6 culture dishes, P<0.05), an increase in [Ca(2+)]i (278±24 nM vs. 71±2 nM in the control, n=60 cells, P<0.05), and the formation of gaps between adjacent EC. These observations indicate that there is impaired barrier function at an early state of metabolic inhibition. Glycolytic inhibition alone by 10mM 2-DG led to a similar decrease in ATP content (14±2 nmol/mg vs. 18±1 nmol/mg in the control, P<0.05) with a delay of 5 min. The [Ca(2+)]i response of EC was biphasic with a peak after 1 min (183±6 nM vs. 71±1 nM, n=60 cells, P<0.05) followed by a sustained increase in [Ca(2+)]i. A 24-h pre-treatment with 10mM of lithium chloride before the inhibition of ATP synthesis abolished both phases of the 2-DG-induced [Ca(2+)]i increase. This effect was not observed when lithium chloride was added simultaneously with 2-DG. We conclude that lithium chloride abolishes the injurious [Ca(2+)]i overload in EC and that this most likely occurs by preventing inositol 3-phosphate-sensitive Ca(2+)-release from the endoplasmic reticulum. Though further research is needed, these findings provide a novel option for therapeutic strategies to protect the endothelium against imminent barrier failure.
- Find related publications in this database (using NLM MeSH Indexing)
- Adenosine Triphosphate - metabolism
- Animals -
- Aorta - cytology
- Calcium - adverse effects
- Calcium Signaling -
- Cells, Cultured -
- Chromatography, High Pressure Liquid -
- Cytosol - drug effects
- Deoxyglucose - pharmacology
- Endoplasmic Reticulum - metabolism
- Endothelial Cells - drug effects
- Fura-2 -
- Glycolysis - drug effects
- Lithium - pharmacology
- Lithium Chloride - metabolism
- Mitochondria - drug effects
- Swine -
- Time Factors -
- Find related publications in this database (Keywords)
- Endothelial cells
- Lithium
- Inositol 3-phosphate-sensitive
- Ca2+-release
- Experimental ischemia
- Endothelial protection