Atorvastatin inhibits GSK-3beta phosphorylation by cardiac hypertrophic stimuli.
In this study we examined the effect of the statin atorvastatin on the Akt/GSK-3beta pathway. Our findings indicate that atorvastatin treatment for 15 days inhibited pressure overload-induced cardiac hypertrophy and prevented nuclear translocation of GATA4 and c-Jun and AP-1 DNA-binding activity. In addition, atorvastatin treatment prevented the increase in the phosphorylation of Akt and GSK-3beta caused by cardiac hypertrophy, and this effect correlated with an increase in protein levels of phosphatase and tensin homolog on chromosome 10 (PTEN), which negatively regulates the phosphoinositide-3 kinase/Akt pathway. To test whether the inhibitory effect of atorvastatin on Akt and GSK-3beta phosphorylation was direct we performed in vitro studies using embryonic rat heart-derived H9c2 cells, human AC16 cardiomyoblasts and neonatal rat cardiomyocytes. Preincubation of cells with atorvastatin prevented Akt/GSK-3beta phosphorylation by different hypertrophic stimuli without affecting PTEN protein levels. However, atorvastatin prevented endogenous reactive oxygen species (ROS) generation and PTEN oxidation, a process that correlates with its inactivation, suggesting that atorvastatin prevents ROS-induced PTEN inactivation in acute treatments. These findings point to a new potential anti-hypertrophic effect of statins, which can prevent activation of the Akt/GSK-3beta hypertrophic pathway by modulating PTEN activation by different mechanisms in chronic and acute treatments.
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, IBUB (Institut de Biomedicina de la UB) and CIBER Diabetes y Enfermedades Metabólicas, Instituto de Salud Carlos III, University of Barcelona, Spain.
Anna
A
Planavila
Ricardo
R
Rodríguez-Calvo
Xavier
X
Palomer
Teresa
T
Coll
Rosa M
RM
Sánchez
Manuel
M
Merlos
Juan C
JC
Laguna
Manuel
M
Vázquez-Carrera
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000831:Animals, Newborn; D000069059:Atorvastatin; D006332:Cardiomegaly / Q000201:enzymology* / Q000503:physiopathology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D050991:GATA4 Transcription Factor / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006538:Heptanoic Acids / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D050991:GATA4 Transcription Factor; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3