Reduction of protein synthesis and statin-induced cardiomyocyte cell death.
The objective of this study was to determine whether an HMG Co A reductase inhibitor (statin) reduces protein synthesis in cardiomyocytes and whether this action maybe an underlying mechanism for statin-induced cell death. Cardiomyocytes from embryonic chick heart were maintained in culture. Cells exposed to lovastatin for 4 h showed a concentration dependent reduction in protein synthesis as assessed by [3H] leucine incorporation and [35S] methionine incorporation. Compared to control, lovastatin 100 microM, which produced a 25% increase in cell death, induced a three-fold reduction in methionine incorporation. [35S] methionine autoradiography showed little (new) protein synthesis at concentrations of lovastatin of 70 microM or higher; an effect that was not limited to specific proteins. Cardiomyocytes treated with lovastatin showed morphologic changes in the nucleoli consistent with insufficient protein synthesis. These cardiomyocytes manifested cell death under conditions of reduced protein synthesis. Interruption of protein synthesis with cycloheximide, a ribosomal RNA transcription inhibitor or reduction in protein substrate availability by lowering the media concentration of fetal calf serum was associated with a concentration-dependent reductions in cell viability. Importantly, stimulation of protein synthesis by higher concentrations of fetal calf serum limited lovastatin-induced cell death. These data suggest that statin-induced inhibition of protein synthesis is an underlying mechanism for statin-induced cell death.
Rabkin
Simon W
SW
University of British Columbia, Level 9, 2775 Laurel St, Vancouver, BC, Canada V5Z 1M9. rabkin@interchange.ubc.ca
Lodha
Parth
P
Kong
Jennifer Y
JY
D000818:Animals; D001345:Autoradiography; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004396:Coloring Agents; D003513:Cycloheximide / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000648:ultrastructure; D011500:Protein Synthesis Inhibitors
D004396:Coloring Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011500:Protein Synthesis Inhibitors; D003513:Cycloheximide; D008148:Lovastatin