Activation of peroxisome proliferator-activated receptor-α prevents glycogen synthase 3β 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-a regulates hypertrophic response. In the present study, we found that application of fenofibrate and overexpression of PPAR-a inhibited endothelin-1 (ET-1)-induced phosphorylation of protein kinase B (Akt) at Ser473 and glycogen synthase kinase3 beta (GSK3 beta) 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-a. These results suggest that activation of PPAR-a inhibits ET-1-induced cardiac hypertrophy through regulating PI3K/Akt/GSK3R and NFAT signaling pathways. (C) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.