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.
Planavila
Anna
A
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.
Rodríguez-Calvo
Ricardo
R
Palomer
Xavier
X
Coll
Teresa
T
Sánchez
Rosa M
RM
Merlos
Manuel
M
Laguna
Juan C
JC
Vázquez-Carrera
Manuel
M
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