The peroxisome proliferator-activated receptor alpha 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 microM) on DNA synthesis in neonatal rat cardiac fibroblasts by [H]thymidine incorporation. The [H]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 [3H]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 by suppressing c-jun expression.
Ogata
Takehiro
T
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
Miyauchi
Takashi
T
Irukayama-Tomobe
Yoko
Y
Takanashi
Masakatsu
M
Goto
Katsutoshi
K
Yamaguchi
Iwao
I
D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D015536:Down-Regulation; D019332:Endothelin-1 / Q000378:metabolism*; D011345:Fenofibrate / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D019332:Endothelin-1; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011345:Fenofibrate