Activation of peroxisome proliferator-activated receptor-alpha prevents glycogen synthase 3beta phosphorylation and inhibits cardiac hypertrophy

FEBS Lett. 2007 Jul 10;581(17):3311-6. doi: 10.1016/j.febslet.2007.06.017. Epub 2007 Jun 19.


Activation of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) has been recently reported to inhibit vascular inflammatory response and prevent cardiac hypertrophy. However, it is unclear how the activation of PPAR-alpha regulates hypertrophic response. In the present study, we found that application of fenofibrate and overexpression of PPAR-alpha inhibited endothelin-1 (ET-1)-induced phosphorylation of protein kinase B (Akt) at Ser473 and glycogen synthase kinase3beta (GSK3beta) at Ser9, and prevented ET-1-induced nuclear translocation of NFATc4 in cardiomyocytes. Moreover, co-immunoprecipitation studies showed that fenofibrate strongly induced the association of nuclear factor of activated T cells (NFATc4) with PPAR-alpha. These results suggest that activation of PPAR-alpha inhibits ET-1-induced cardiac hypertrophy through regulating PI3K/Akt/GSK3beta and NFAT signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cardiomegaly / enzymology
  • Cardiomegaly / prevention & control*
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Endothelin-1 / physiology
  • Fenofibrate / pharmacology*
  • Gene Expression Regulation
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • NFATC Transcription Factors / metabolism
  • Nerve Tissue Proteins / metabolism
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*
  • Phosphorylation / drug effects
  • Protein Transport / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Transfection


  • Endothelin-1
  • NFATC Transcription Factors
  • Nerve Tissue Proteins
  • Nfatc4 protein, rat
  • PPAR alpha
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Glycogen Synthase Kinase 3
  • Fenofibrate