Aldose reductase induced by hyperosmotic stress mediates cardiomyocyte apoptosis: differential effects of sorbitol and mannitol.
Cells adapt to hyperosmotic conditions by several mechanisms, including accumulation of sorbitol via induction of the polyol pathway. Failure to adapt to osmotic stress can result in apoptotic cell death. In the present study, we assessed the role of aldose reductase, the key enzyme of the polyol pathway, in cardiac myocyte apoptosis. Hyperosmotic stress, elicited by exposure of cultured rat cardiac myocytes to the nonpermeant solutes sorbitol and mannitol, caused identical cell shrinkage and adaptive hexose uptake stimulation. In contrast, only sorbitol induced the polyol pathway and triggered stress pathways as well as apoptosis-related signaling events. Sorbitol resulted in activation of the extracellular signal-regulated kinase (ERK), p54 c-Jun N-terminal kinase (JNK), and protein kinase B. Furthermore, sorbitol treatment resulting in induction and activation of aldose reductase, decreased expression of the antiapoptotic protein Bcl-xL, increased DNA fragmentation, and glutathione depletion. Apoptosis was attenuated by aldose reductase inhibition with zopolrestat and also by glutathione replenishment with N-acetylcysteine. In conclusion, our data show that hypertonic shrinkage of cardiac myocytes alone is not sufficient to induce cardiac myocyte apoptosis. Hyperosmolarity-induced cell death is sensitive to the nature of the osmolyte and requires induction of aldose reductase as well as a decrease in intracellular glutathione levels.
Galvez
Anita S
AS
Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 6640750, Chile.
Ulloa
Juan Alberto
JA
Chiong
Mario
M
Criollo
Alfredo
A
Eisner
Verónica
V
Barros
Luis Felipe
LF
Lavandero
Sergio
S
D000449:Aldehyde Reductase / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001692:Biological Transport; D015153:Blotting, Western; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005947:Glucose / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008353:Mannitol / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D009995:Osmosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013012:Sorbitol / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D051020:bcl-X Protein; D048051:p38 Mitogen-Activated Protein Kinases
D000449:Aldehyde Reductase; D005947:Glucose; D005978:Glutathione; D048031:JNK Mitogen-Activated Protein Kinases; D008353:Mannitol; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D013012:Sorbitol; D051020:bcl-X Protein; D048051:p38 Mitogen-Activated Protein Kinases; C494813:Bcl2l1 protein, rat