Abstract
1. The clinical use of doxorubicin is limited by the development of severe cardiomyopathies linked, at least in part, to an abnormal increase in the rate of apoptotic cell death. Because cell shrinkage is considered to be a crucial step at the onset of apoptosis, the aim of the present study was to investigate whether a brief hypo-osmotic stress, which leads to an increase in cell volume, could interfere with the induction of apoptosis by doxorubicin in adult cardiomyocytes. 2. Cell volume expansion results in intracellular accumulation of cAMP, so we secondarily tested whether the protective effect of hypo-osmotic stress could be related to the cAMP pathway. Accordingly, apoptosis was induced by doxorubicin (1 micromol/L) in cardiomyocytes freshly isolated from New Zealand adult rabbit hearts. 3. Exposure to doxorubicin in an iso-osmotic medium (290 mOsmol/kg H2O) induced a rapid decrease in cell volume, as well as increases in annexin V labelling and caspase-3 activity, two biological markers of apoptosis. These effects of doxorubicin were abolished by 15 min pretreatment with hypo-osmotic stress at 220 mOsmol/kgH2O (HS 220). 4. This cytoprotective effect of HS 220 was still observed when doxorubicin was added to the medium 6...Continue Reading
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