Activation of peroxisome proliferator-activated receptor-alpha prevents glycogen synthase 3beta phosphorylation and inhibits cardiac hypertrophy.
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.
Li
Ruifang
R
Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
Zheng
Wenhua
W
Pi
Rongbiao
R
Gao
Jie
J
Zhang
Huijie
H
Wang
Ping
P
Le
Kang
K
Liu
Peiqing
P
D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000201:enzymology / Q000517:prevention & control*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000502:physiology; D011345:Fenofibrate / Q000494:pharmacology*; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D019332:Endothelin-1; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C477593:Nfatc4 protein, rat; D047493:PPAR alpha; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D011345:Fenofibrate