The peroxisome proliferator-activated receptor α activator fenofibrate inhibits endothelin-1-induced cardiac fibroblast proliferation

Endothelin-1 has been known to promote tissue fibrosis. We previously reported in our animal experiments that a peroxisome proliferator-activated receptor alpha (PPARalpha) inhibited cardiac fibrosis with suppression of endothelin-1 production, and it was also reported that PPARalpha activation suppressed the production of c-jun, which is a component of activator protein-1. The objective of this study is to clarify on the in vitro level that PPARalpha activators inhibited cardiac fibroblast proliferation via their suppressive action on c-jun expression. We investigated the effects of the PPARalpha activator fenofibrate (10 muM) on DNA synthesis in neonatal rat cardiac fibroblasts by [H-3]thymidine incorporation. The [H-3]thymidine incorporation in cardiac fibroblasts showed an increase of 1.1-fold by endothelin-1 (10(-8)M) stimulation. Fenofibrate treatment showed significant inhibition of [H-3]thymidine incorporation in both endothelin-1-stimulated and non-stimulated fibroblasts. Additionally, we also evaluated mRNA expressions of c-jun and c-fos in the fibroblasts by the reverse transcription-polymerase chain reaction method. Fenofibrate treatment markedly reduced c-jun mRNA expression, whereas it did not affect c-fos mRNA expression. In conclusion, we demonstrated that the PPARalpha activator fenofibrate inhibited endothelin-1-induced proliferation of cardiac fibroblasts and also inhibited non-stimulated proliferation. This inhibition of proliferation may be caused by up-regulation of p27(Kip1) by suppressing c-jun expression.