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Atorvastatin inhibits GSK-3beta phosphorylation by cardiac hypertrophic stimuli

Anna Planavila1, Ricardo Rodríguez-Calvo, Xavier Palomer

  • 1Pharmacology 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.

Biochimica Et Biophysica Acta
|November 27, 2007
PubMed

Insights

Atorvastatin, a statin, inhibits cardiac hypertrophy by blocking the Akt/GSK-3beta pathway. It also modulates PTEN activation, offering a new anti-hypertrophic effect for statins.

Area of Science:

  • Cardiovascular Research
  • Molecular Biology
  • Pharmacology

Background:

  • Cardiac hypertrophy is a significant risk factor for heart failure.
  • The Akt/GSK-3beta pathway plays a crucial role in cardiac hypertrophy.
  • PTEN (phosphatase and tensin homolog on chromosome 10) negatively regulates the phosphoinositide-3 kinase/Akt pathway.

Purpose of the Study:

  • To investigate the effect of atorvastatin on the Akt/GSK-3beta pathway in cardiac hypertrophy.
  • To explore the mechanisms underlying atorvastatin's action on PTEN and reactive oxygen species (ROS).

Main Methods:

  • In vivo study: 15-day atorvastatin treatment in a pressure overload-induced cardiac hypertrophy model.
  • In vitro studies: H9c2 cells, AC16 cardiomyoblasts, and neonatal rat cardiomyocytes treated with atorvastatin.
  • Assays: Western blotting for protein levels, DNA-binding activity assays, ROS detection, and PTEN oxidation assessment.

Main Results:

  • Atorvastatin inhibited cardiac hypertrophy, GATA4/c-Jun nuclear translocation, and AP-1 DNA-binding activity.
  • Atorvastatin prevented the increase in Akt and GSK-3beta phosphorylation, correlating with increased PTEN protein levels.
  • In vitro, atorvastatin prevented Akt/GSK-3beta phosphorylation and ROS generation, suggesting prevention of PTEN inactivation by ROS.

Conclusions:

  • Atorvastatin exhibits a novel anti-hypertrophic effect by inhibiting the Akt/GSK-3beta pathway.
  • Atorvastatin modulates PTEN activation through different mechanisms in chronic (protein level) and acute (ROS-mediated inactivation) treatments.
  • These findings suggest statins may have therapeutic potential beyond lipid-lowering in managing cardiac hypertrophy.

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