Anti-apoptotic effect of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, on cardiac myocytes through protein kinase C activation.
Pleiotropic effects of statins, which are independent of lipid lowering, have been reported. In the present study, we examined the effect of a statin on apoptosis of adult rat cultured cardiac myocytes. We used the protein kinase C (PKC) inhibitors staurosporine (1 micro mol/L), chelerythrine (10 micro mol/L) and rottlerin (5 micro mol/L) to induce myocyte apoptosis. The effect of atorvastatin (10(-7) g/mL), a statin, on myocyte apoptosis induced by these PKC inhibitors was examined. All these PKC inhibitors markedly increased the percentage of terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL)-positive myocytes. This increase was significantly suppressed by atorvastatin treatment. Both chelerythrine and rottlerin induced subcellular translocation of PKCdelta and elevated caspase-3 activity in myocytes. The changes in the subcellular distribution of PKCdelta and caspase-3 activity induced by these PKC inhibitors were suppressed by atorvastatin treatment. The results of the present study suggest that the inhibitory effect of atorvastatin on apoptosis of adult rat cardiac myocytes induced by the PKC inhibitors is through activation of PKCdelta pathway.
Tanaka
Koichi
K
The 4th Department of Internal Medicine, Shimane Medical University, Shimane, Japan.
Honda
Masaaki
M
Takabatake
Toshikazu
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D000069059:Atorvastatin; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D011493:Protein Kinase C / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D011493:Protein Kinase C