Statins induce calcium-dependent mitochondrial permeability transition.
Statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) are used in the treatment of hypercholesterolemic patients to reduce risk of cardiovascular diseases because of their cholesterol lowering action. Other lipid independent protective actions of statins have been reported. However, some adverse side effects have, also, been described. We report, here, that liver mitochondria isolated from hypercholesterolemic LDL receptor knockout mice treated during 15 days with therapeutic doses (100 mg/kg, p.o.) of lovastatin presented a higher susceptibility to develop membrane permeability transition (MPT). In experiments in vitro, lovastatin-induced MPT in a dose-dependent manner (10-80 microM) by a mechanism sensitive to cyclosporin A (cyclophilin sequestrant), dithiothreitol (reducing agent), adenine nucleotide carrier inhibitor (ADP), catalase (H2O2 reductant) and EGTA (calcium chelator). In agreement with the inhibition of the mitochondrial swelling by dithiothreitol, lovastatin, also, decreased the content of total mitochondrial membrane protein thiol groups. Simvastatin had similar effects on mitochondria; however, pravastatin, a hydrophilic statin, had a weaker effect in inducing MPT. In conclusion, statins can act directly on mitochondria either in vivo or in vitro inducing permeability transition, which is a process involved in cell death.
Velho
Jesus A
JA
Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), 13083-970 Campinas, São Paulo, Brazil.
Okanobo
Heitor
H
Degasperi
Giovanna R
GR
Matsumoto
Márcio Y
MY
Alberici
Luciane C
LC
Cosso
Ricardo G
RG
Oliveira
Helena C F
HC
Vercesi
Anibal E
AE
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D002374:Catalase / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D004229:Dithiothreitol / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004594:Electrophysiology; D006614:Hindlimb / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008148:Lovastatin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects*; D008931:Mitochondria, Muscle / Q000187:drug effects*; D008933:Mitochondrial Swelling / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D010619:Phenazines; D011506:Proteins / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013439:Sulfhydryl Reagents / Q000494:pharmacology
D002614:Chelating Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010619:Phenazines; D011506:Proteins; D011973:Receptors, LDL; D013438:Sulfhydryl Compounds; D013439:Sulfhydryl Reagents; D004533:Egtazic Acid; D000244:Adenosine Diphosphate; D002784:Cholesterol; D008148:Lovastatin; D002374:Catalase; D004229:Dithiothreitol; C009195:safranine T